Cftr regulators and methods of use thereof

ABSTRACT

Provided herein are compounds that activate CFTR and methods for treating constipation, dry eye disorders or other diseases and disorders.

CROSS-REFERENCES TO RELATED APPLICATIONS

This application is a divisional application of U.S. application Ser.No. 16/016,300, filed on Jun. 22, 2018, which is a 371 application ofInternational Application No. PCT/US2016/068561, filed on Dec. 23, 2016,which claims the benefit under 35 U.S.C. § 119(e) of U.S. ProvisionalApplication No. 62/387,591, filed on Dec. 24, 2015, which applicationsare incorporated by reference herein in their entirety and for allpurposes.

STATEMENT AS TO RIGHTS TO INVENTIONS MADE UNDER FEDERALLY SPONSOREDRESEARCH AND DEVELOPMENT

This invention was made with the government support under Grant Nos.TR000004, EY023981, EY013574, EB000415, DK035124, DK072517 and DK101373,awarded by the National Institutes of Health. The government has certainrights in the invention.

BACKGROUND OF THE INVENTION

Constipation is a common clinical complaint in adults and children thatnegatively impacts quality of life. The prevalence of chronicconstipation has been estimated to be 15% in the U.S. population, withhealth-care costs estimated at approximately 7 billion dollars annually,with in excess of 500 million dollars spent on laxatives. The mainstayof constipation therapy includes laxatives and many of them areavailable over the counter (soluble fiber, polyethylene glycol,probiotics, etc.). There are two FDA-approved chloride channelactivators, lubiprostone and linaclotide, for treatment of constipation,but clinical trials showed variable and unimpressive efficacy of bothdrugs. Despite the wide range of therapeutic options, there is acontinued need for safe and effective drugs to treat constipation.

Dry eye is a heterogeneous tear film disorder that results in eyediscomfort, visual disturbance, and ocular surface pathology, andremains an unmet need in ocular disease with limited effectivetherapeutic options available. Dry eye is a major public health concernin an aging population, affecting up to one-third of the globalpopulation, including 5 million Americans aged 50 and over.Over-the-counter artificial tears and implantable punctal plugs arefrequently used for symptomatic relief. Therapeutic approaches involvereducing ocular surface inflammation or augmenting tear/mucin secretion.The only medication currently approved for dry eye is topicalcyclosporine, an anti-inflammatory that does not eliminate all symptomsin most dry eye patients. Accordingly, additional treatments are neededfor moderate-to-severe dry eye. Described herein, inter alia, aresolutions to these and other problems in the art.

BRIEF SUMMARY OF THE INVENTION

Provided herein are compounds having the formula:

In the compound of formula (I), Ar is substituted or unsubstituted arylor substituted or unsubstituted heteroaryl. L¹ and L² are independentlysubstituted or unsubstituted (e.g. C₁-C₁₀; C₁-C₅, or C₁-C₃) alkylene. R¹is hydrogen, halogen, —CX^(1.1) ₃, —CHX^(1.1) ₂, —CH₂X^(1.1), —CN,—SO_(n1)R^(1A), —SO_(v1)NR^(1B)R^(1C), —NHNR^(1B)R^(1C),—ONR^(1B)R^(1C), —NHC(O)NHNR^(1B)R^(1C), —NHC(O)NR^(1B)R^(1C),—N(O)_(m1), —NR^(1B)R^(1C), —C(O)R^(1D), —C(O)OR^(1D),—C(O)NR^(1B)R^(1C), —OR^(1A), —NR^(1B)SO₂R^(1A), —NR^(1B)C(O)R^(1D),—NR^(1B)C(O)OR^(1D), —NR^(1B)OR^(1D), —OCX^(1.1) ₃, —OCHX^(1.1) ₂,substituted or unsubstituted alkyl, substituted or unsubstitutedheteroalkyl, substituted or unsubstituted cycloalkyl, substituted orunsubstituted heterocycloalkyl, substituted or unsubstituted aryl, orsubstituted or unsubstituted heteroaryl. R² is hydrogen, halogen,—CX^(2.1) ₃, —CHX^(2.1) ₂, —CH₂X^(2.1), —CN, —SO_(n2)R^(2A),—SO_(v2)NR^(2B)R^(2C), —NHNR^(2B)R^(2C), —ONR^(2B)R^(2C),—NHC(O)NHNR^(2B)R^(2C), —NHC(O)NR^(2B)R^(2C), —N(O)_(m2),—NR^(2B)R^(2C), —C(O)R^(2D), —C(O)OR^(2D), —C(O)NR^(2B)R^(2C), —OR^(2A),—NR^(2B)SO₂R^(2A), —NR^(2B)C(O)R^(2D), —NR^(2B)C(O)OR^(2D),—NR^(2B)OR^(2D), —OCX^(2.1) ₃, —OCHX^(2.1) ₂, substituted orunsubstituted alkyl, substituted or unsubstituted heteroalkyl,substituted or unsubstituted cycloalkyl, substituted or unsubstitutedheterocycloalkyl, substituted or unsubstituted aryl, or substituted orunsubstituted heteroaryl. R³ is hydrogen, halogen, —CX^(3.1) ₃,—CHX^(3.1) ₂, —CH₂X^(3.1), —CN, —SO_(n3)R^(3A), —SO_(v3)NR^(3B)R^(3C),—NHNR^(3B)R^(3C), —ONR^(3B)R^(3C), —NHC(O)NHNR^(3B)R^(3C),—NHC(O)NR^(3B)R^(3C), —N(O)_(m3), —NR^(3B)R^(3C), —C(O)R^(3D),—C(O)OR^(3D), —C(O)NR^(3B)R^(3C), —OR^(3A), —NR^(3B)SO₂R^(3A),—NR^(3B)C(O)R^(3D), —NR^(3B)C(O)OR^(3D), —NR^(3B)OR^(3D), —OCX^(3.1) ₃,—OCHX^(3.1) ₂, substituted or unsubstituted alkyl, substituted orunsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl,substituted or unsubstituted heterocycloalkyl, substituted orunsubstituted aryl, or substituted or unsubstituted heteroaryl. R⁴ ishydrogen, halogen, —CX^(4.1) ₃, —CHX^(4.1) ₂, —CH₂X^(4.1), —CN,—SO_(n4)R^(4A), —SO_(v4)NR^(4B)R^(4C), —NHNR^(4B)R^(4C),—ONR^(4B)R^(4C), —NHC(O)NHNR^(4B)R^(4C), —NHC(O)NR^(4B)R^(4C),—N(O)_(m4), —NR^(4B)R^(4C), —C(O)R^(4D), —C(O)OR^(4D),—C(O)NR^(4B)R^(4C), —OR^(4A), —NR^(4B)SO₂R^(4A), —NR^(4B)C(O)R^(4D),—NR^(4B)C(O)OR^(4D), —NR^(4B)OR^(4D), —OCX^(4.1) ₃, —OCHX^(4.1) ₂,substituted or unsubstituted alkyl, substituted or unsubstitutedheteroalkyl, substituted or unsubstituted cycloalkyl, substituted orunsubstituted heterocycloalkyl, substituted or unsubstituted aryl, orsubstituted or unsubstituted heteroaryl. R⁵ is hydrogen, halogen,—CX^(5.1) ₃, —CHX^(5.1) ₂, —CH₂X^(5.1), —CN, —SO_(n5)R^(5A),—SO_(v5)NR^(5B)R^(5C), —NHNR^(5B)R^(5C), —ONR^(5B)R^(5C),—NHC(O)NHNR^(5B)R^(5C), —NHC(O)NR^(5B)R^(5C), —N(O)_(m5),—NR^(5B)R^(5C), —C(O)R^(5D), —C(O)OR^(5D), —C(O)NR^(5B)R^(5C), —OR^(5A),—NR^(5B)SO₂R^(5A), —NR^(5B)C(O)R^(5D), —NR^(5B)C(O)OR^(5D),—NR^(5B)OR^(5D), —OCX^(5.1) ₃, —OCHX^(5.1) ₂, substituted orunsubstituted alkyl, substituted or unsubstituted heteroalkyl,substituted or unsubstituted cycloalkyl, substituted or unsubstitutedheterocycloalkyl, substituted or unsubstituted aryl, or substituted orunsubstituted heteroaryl. R^(1A), R^(1B), R^(1C), R^(1D), R^(2A),R^(2B), R^(2C), R^(2D), R^(3A), R^(3B), R^(3C), R^(3D), R^(4A), R^(4B),R^(4C), R^(4D), R^(5A), R^(5B), R^(5C) and R^(5D) are independentlyhydrogen, halogen, —CF₃, —CCl₃, —CBr₃, —CI₃, —OH, —NH₂, —COOH, —CONH₂,—NO₂, —SH, —SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂, —ONH₂, —NHC(O)NHNH₂,—NHC(O)NH₂, —NHSO₂H, —NHC(O)H, —NHC(O)—OH, —NHOH, —OCF₃, —OCCl₃, —OCBr₃,—OCI₃, —OCHF₂, —OCHCl₂, —OCHBr₂, —OCHI₂, substituted or unsubstitutedalkyl, substituted or unsubstituted heteroalkyl, substituted orunsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl,substituted or unsubstituted aryl, or substituted or unsubstitutedheteroaryl; R^(1B), R^(1C), R^(2B), R^(2C), R^(3B), R^(3C), R^(4B),R^(4C), R^(5B) and R^(5C) substituents bonded to the same nitrogen atommay optionally be joined to form a substituted or unsubstitutedheterocycloalkyl or substituted or unsubstituted heteroaryl. X^(1.1),X^(2.1), X^(3.1), X^(4.1) and X^(5.1) are independently —Cl, —Br, —I or—F. The symbol n1, n2, n3, n4 and n5 are independently an integer from 0to 4. The symbols m1, m2, m3, m4, m5, v1, v2, v3, v4 and v5 areindependently 1 or 2.

Also provided herein are pharmaceutical compositions. In one aspect is apharmaceutical composition that includes a compound described herein anda pharmaceutically acceptable excipient.

Further provided herein are methods of activating Cystic FibrosisTransmembrane Conductance Regulator (CFTR) by contacting CFTR with aneffective amount of the compound described herein, thereby activatingCFTR.

Further provided herein are methods of treating a disease or disorder ina subject in need thereof by administering an effective amount of acompound as described herein. In one aspect is a method of treatingconstipation in a subject in need thereof, the method includingadministering to the subject an effective amount of a compound asdescribed herein. In another aspect, is a method of treating a dry eyedisorder in a subject in need thereof, the method includingadministering to the subject an effective amount of a compound asdescribed herein. In yet another aspect, is a method of increasinglacrimation in a subject in need thereof, the method includingadministering to the subject an effective amount a compound as describedherein.

In one aspect, provided is a method of treating a cholestatic liverdisease in a subject in need thereof, including administering to thesubject an effective amount a compound as described herein. In anotheraspect, provided is a method of treating a pulmonary disease or disorderin a subject in need thereof, including administering to the subject aneffective amount of a compound as described herein. In embodiments, thepulmonary disease or disorder is chronic obstructive pulmonary disease(e.g. bronchitis, asthma, cigarette smoke-induced lung dysfunction).

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1. Strategy for pre-clinical development of CFTR activators for dryeye therapy. Activators of human wild-type CFTR activators identified byhigh-throughput screening are confirmed and characterized using byelectrophysiological and biochemical assays, and then tested in livemice for activity at the ocular surface by measurements of potentialdifference and tear fluid secretion. The best compounds are then testedfor pharmacokinetic properties and efficacy in a dry eye rodent model.

FIGS. 2A-2D. In vitro characterization of CFTR activators. FIG. 2A)(Top) Chemical structures. (Bottom) Representative short-circuit current(I_(sc)) measured in Fischer rat thyroid (FRT) cells expressingwild-type CFTR. CFTR current was stimulated by test compounds andforskolin, and inhibited by CFTR_(inh)-172 (10 μM). FIG. 2B)Concentration-dependence of CFTR activators (each data set derived froma single dose-response experiment as in A and fitted using anexponential curve). One-hundred percent CFTR activation is defined asthat produced by 20 μM forskolin. FIG. 2C) I_(sc) measurement for VX-770done as in A. FIG. 2D) Cellular cAMP concentration in FRT cells inresponse to incubation for 10 min with 5 μM test compounds without orwith forskolin (fsk, 100 nM). Positive controls included forskolin (100nM and 20 μM), and forskolin plus 3-isobutyl-1-methylxanthine (IBMX, 100μM) (mean±SEM, n=4-8).

FIGS. 3A-3E. Potential difference (PD) measurements of CFTR activatorsat the ocular surface in live mice. FIG. 3A) (Left) Photograph of ananesthetized mouse demonstrating ocular surface perfusion for PDmeasurement. The perfusion catheter, attached to the measuringelectrode, is oriented perpendicular to the ocular surface.Cross-clamping forceps retract the upper eyelid to expose cornea andbulbar/palbebral conjunctiva for perfusion. The reference electrode isgrounded via subcutaneous butterfly needle. (Right) Schematic of PDtracing for a typical experiment testing CFTR activity, as described inResults. FIG. 3B) Representative ocular surface PD measurements inwild-type mice. Solution compositions are detailed in Ref. 22.Concentrations: amiloride, 100 μM; forskolin and CFTR_(inh)-172, 10 μM;test compounds, 1-10 μM as indicated. FIG. 3C) Study as in C, but withVX-770, 1-10 μM, as indicated. FIG. 3D) Summary of ΔPD in wild-type miceproduced by forskolin (20 μM), or test compounds or VX-770 (each 1 μM).PDs were recorded in the presence of 100 μM amiloride and in thepresence of an outward apical Cl⁻ gradient (mean±SEM, 8-20 eyes peragonist tested). FIG. 3E) Representative ocular surface PD measurementsin CF mouse. Study as in B & C, CFTR_(act)-K032, 1-10 μM as indicated.

FIGS. 4A-4D. Tear fluid secretion measurement of CFTR activators inliving mice. FIG. 4A) Tear fluid was measured just prior to and atindicated times after single-dose topical application of vehicle (PBS,0.5% polysorbate, 0.5% DMSO), cholera toxin (0.1 μg/mL), forskolin (20μM), or forskolin+IBMX (250 μM). The effect of cholera toxin wasmeasured after pre-anesthetizing the ocular surface with 4% lidocaine tosuppress irritation and reflex tear secretion (mean±SEM, 6-10 eyes percondition). FIG. 4B) Time course of tear secretion following topicaldelivery of indicated compound. Concentrations: CFTR_(act)-B074, 100 μM;CFTR_(act)-J027, 50 μM; CFTR_(act)-K089, 50 μM; VX-770, 10 μM (mean±SEM,6-18 eyes). FIG. 4C) Effect of repeated dosing. CFTR_(act)-J027 (0.1nmol) was topically applied three times a day for two days. Tear fluidmeasurements were done after Dose 1 and Dose 2 on day 1, and Dose 5 onday 2 (mean±SEM, n=6 eyes). FIG. 4D) Lack of effect of CFTR activatorson tear fluid secretion in CF mice, with compounds tested at the sameconcentrations as in B.

FIGS. 5A-5C. Compound pharmacology. FIG. 5A) Liquid chromatography/massspectroscopy (LC/MS) determination of CFTR_(act)-K089 amount in tearfluid at indicated times following single-dose (0.1 nmol)administration. Representative background-subtracted peak areas fromtear washes (left) and means of corresponding amount recovered (right)(mean±SEM, 4 eyes per time point). Dashed lines denote the upper andlower calculated quantities of CFTR_(act)-K089 required to achieve EC₅₀concentration. FIG. 5B) Lissamine green staining of cornea in BALB/cmice, measured on a 12-point scale (see Methods) after 14-days of threetimes daily treatment with CFTR activators (0.1 nmol) or vehicle(mean±SEM, 6 eyes per group). Shown as a positive control are scoresfrom vehicle-treated mice following lacrimal gland excision (LGE) on Day0 (n=11 eyes; *P<0.001 compared with other groups). FIG. 5C)Cytotoxicity measured by Alamar Blue assay in FRT cells incubated withtest compounds for 1 or 24 h (10% DMSO as positive control; *P<0.05compared to untreated cells; P=0.02 and 0.0006 for 1 and 24 h,respectively) (mean±SEM, n=4).

FIGS. 6A-6C. Topical CFTR_(act)-K089 restores tear secretion andprevents corneal epithelial disruption following LGE. FIG. 6A) Basaltear secretion following extraorbital LGE in BALB/c mice, comparing eyestreated with CFTR_(act)-K089 (mean±SEM, 15 eyes) to vehicle (n=11 eyes).Tear volume was measured immediately prior to LGE, and then one hourafter the first daily dose on Days 4, 10 and 14 after LGE. *P<0.001.FIG. 6B) Representative photographs of eyes prior to LGE (left) and onDay 14 after LGE (right) in vehicle-treated eyes (top) andCFTR_(act)-K089-treated eyes (bottom). FIG. 6C) Corneal epithelialdisruption after LGE measured by LG scoring on a 12-point scale in thesame eyes as in A (mean±SEM). *P<0.001.

FIG. 7. A summary of EC₅₀ and V_(max) values for compounds screenedagainst CFTR A cell-based functional high-throughput screen of 120,000compounds at 10 μM identified 20 chemical classes of small-moleculeactivators of wild-type CFTR that produced >95% of maximal CFTRactivation. The screen was done in FRT epithelial cells co-expressinghuman wild-type CFTR and a cytoplasmic YFP halide sensor in 96-wellformat (26, 31, 32). Details of the primary screen will be reportedseparately. Secondary screening involved I_(sc) measurement inCFTR-expressing FRT cells pretreated with submaximal forskolin (50 nM).Twenty-one compounds from eight chemical classes produced largeincreases in I_(sc) at 1 μM (>75% of maximal current produced by 20 μMforskolin).

FIGS. 8A-8D. Identification of small-molecule CFTR activators. FIG. 8A.Project overview. FIG. 8B. CFTR activator screen using FRT cellscoexpressing human wild-type CFTR and YFP iodide-sensing protein. Testcompounds at 10 μM were added for 10 min at room temperature in thepresence of forskolin (125 nM) before iodide addition. Examples of datafrom single wells of a 96-well plate showing CFTR activation byCFTR_(act)-J027. FIG. 8C. Structures of CFTR activators emerging fromthe screen. FIG. 8D. Synthesis of CFTR_(act)-J027.

FIGS. 9A-9E. Characterization of CFTR activation by CFTR_(act)-J027.Short-circuit current measured in FRT cells expressing human wild-typeCFTR (FIG. 9A) and ΔF508-CFTR (FIG. 9C) showing responses to indicatedconcentrations of forskolin (fsk), CFTR_(act)-J027, and VX-770. TheΔF508-CFTR-expressing FRT cells were corrected with 3 μM VX-809 at 37°C. for 24 h before measurement. CFTR_(inh)-172 (Inh-172, 10 μM) wasadded where indicated. FIG. 9B. CFTR_(act)-J027 concentration-dependentactivation of wild-type CFTR Cl⁻ current (S.E.; n=3 cultures). FIG. 9D.Short-circuit current in mouse colon showing responses to indicatedconcentrations of forskolin (fsk), CFTR_(act)-J027, and CFTR_(inh)-172.FIG. 9E. Assay of cAMP concentration in FRT cells measured following10-min incubation with indicated concentrations of forskolin and 5 μMCFTR_(act)-J027. Positive controls included forskolin (100 nM and 20μM), and forskolin plus 3-isobutyl-1-methylxanthine (IBMX, 100 μM)(mean±SE, n=4-8).

FIGS. 10A-10D. CFTR_(act)-J027 normalizes stool output and water contentin loperamide-treated mice. FIG. 10A. Mouse model of constipation withloperamide (left). Three-hour stool weight, number of pellets, and stoolwater content in mice (mean±S.E., 6 mice per group). FIG. 10B. Samestudy as in A, but with cystic fibrosis mice lacking function CFTR (3-6mice per group). FIG. 10C. Same study in A, but with an inactivechemical analog of CFTR_(act)-J027 (structure shown). FIG. 10D.Dose-response for intraperitoneal administration of CFTR_(act)-J027 inloperamide-treated mice (4-6 mice per group). One-way analysis ofvariance was used for A and B, Student's t-test was used for C, *p<0.05,***p<0.001, ns: not significant.

FIGS. 11A-11C. Orally administered CFTR_(act)-J027 normalizes stooloutput and water content in loperamide-treated mice. FIG. 11A. Studyprotocol (left) and stool output, pellet number and water content asdone in FIG. 3 (mean±S.E., 6 mice per group). FIG. 11B. Dose-responsestudy of CFTR_(act)-J027 administered orally in loperamide-treated mice(4-6 mice per group). FIG. 11C. Same study in FIG. 11A, but with orallubiprostone (0.5 mg/kg) or linaclotide (0.5 mg/kg) (5-6 mice pergroup). One-way analysis of variance, *p<0.05, **p<0.01, ***p<0.001, ns:not significant.

FIGS. 12A-12D. CFTR_(act)-J027 actions on intestinal fluid secretion,absorption and motility. FIG. 12A. Whole-gut transit time in control andloperamide-treated wild-type (left) and cystic fibrosis (right) mice(mean±S.E., 3-5 mice per group). Where indicated loperamide (0.3 mg/kg)and CFTR_(act)-J027 (10 mg/kg) was administered intraperitoneally at 0time (mean±S.E., 6 mice per group). One-way analysis of variance,**p<0.01, ***p<0.001, ns: not significant.

FIG. 12B. Contraction of isolated intestinal strips. Ileum and colonstrips (2 cm) were suspended in Krebs-Henseleit buffer with 0.5 g and0.2 g tension, respectively. Where indicated CFTR_(act)-J027, loperamideand carbachol were added to the organ chamber. FIG. 12C. Intestinalfluid secretion measured in closed mid-jejunal loops in wild-type mice(upper panel). Loops were injected with 100 μL vehicle or 100 μgCFTR_(act)-J027. Loop weight/length was measured at 90 min (mean±S.E., 4loops per group). Similar experiments done in cystic fibrosis mice(lower panel). FIG. 12D. Intestinal fluid absorption measured inmid-jejunal loops in cystic fibrosis mice. Loops were injected with 100μL vehicle or 0.1 mg CFTR_(act)-J027. Loop weight/length was measured at30 min. Summary of fluid absorption (mean±S.E., 4 loops per group).Student's t-test, **p<0.01, ***p<0.001, ns: not significant.

FIGS. 13A-13E. CFTR_(act)-J027 pharmacokinetics, tissue distribution andtoxicity. FIG. 13A. In vitro metabolic stability of CFTR_(act)-J027assayed in mouse liver microsomes after incubation for specified times.FIG. 13B. Standard plasma concentration curve for LC-MS (left) andkinetics of CFTR_(act)-J027 concentration in plasma determined by LC/MSfollowing bolus intraperitoneal or oral administration of 10 mg/kgCFTR_(act)-J027 at zero time (right, mean±S.E., 3 mice per group). FIG.13C. In vitro toxicity measured by Alamar Blue assay in FRT cells.

FIG. 13D. Body weight and lung wet/dry weight ratio in mice receiving 10mg/kg CFTR_(act)-J027 orally for 7 days (mean±S.E., 5 mice per group).FIG. 13E. Chronic administration protocol (left) and efficacy of oralCFTR_(act)-J027 after 7-day administration (mean±S.E., 5 mice pergroup). Student's t-test, *p<0.05, **p<0.01, ***p<0.001, ns: notsignificant.

DETAILED DESCRIPTION OF THE INVENTION

The abbreviations used herein have their conventional meaning within thechemical and biological arts. The chemical structures and formulae setforth herein are constructed according to the standard rules of chemicalvalency known in the chemical arts.

Where substituent groups are specified by their conventional chemicalformulae, written from left to right, they equally encompass thechemically identical substituents that would result from writing thestructure from right to left, e.g., —CH₂O— is equivalent to —OCH₂—.

The term “alkyl,” by itself or as part of another substituent, means,unless otherwise stated, a straight (i.e., unbranched) or branchedcarbon chain (or carbon), or combination thereof, which may be fullysaturated, mono- or polyunsaturated and can include mono-, di- andmultivalent radicals, having the number of carbon atoms designated(i.e., C₁-C₁₀ means one to ten carbons). Alkyl is an uncyclized chain.Examples of saturated hydrocarbon radicals include, but are not limitedto, groups such as methyl, ethyl, n-propyl, isopropyl, n-butyl, t-butyl,isobutyl, sec-butyl, (cyclohexyl)methyl, homologs and isomers of, forexample, n-pentyl, n-hexyl, n-heptyl, n-octyl, and the like. Anunsaturated alkyl group is one having one or more double bonds or triplebonds. Examples of unsaturated alkyl groups include, but are not limitedto, vinyl, 2-propenyl, crotyl, 2-isopentenyl, 2-(butadienyl),2,4-pentadienyl, 3-(1,4-pentadienyl), ethynyl, 1- and 3-propynyl,3-butynyl, and the higher homologs and isomers. An alkoxy is an alkylattached to the remainder of the molecule via an oxygen linker (—O—).

The term “alkylene,” by itself or as part of another substituent, means,unless otherwise stated, a divalent radical derived from an alkyl, asexemplified, but not limited by, —CH₂CH₂CH₂CH₂—. Typically, an alkyl (oralkylene) group will have from 1 to 24 carbon atoms, with those groupshaving 10 or fewer carbon atoms being preferred in the presentinvention. A “lower alkyl” or “lower alkylene” is a shorter chain alkylor alkylene group, generally having eight or fewer carbon atoms. Theterm “alkenylene,” by itself or as part of another substituent, means,unless otherwise stated, a divalent radical derived from an alkene.

The term “heteroalkyl,” by itself or in combination with another term,means, unless otherwise stated, a stable straight or branched chain, orcombinations thereof, including at least one carbon atom and at leastone heteroatom (e.g., selected from the group consisting of O, N, P, Si,and S), and wherein the nitrogen and sulfur atoms may optionally beoxidized, and the nitrogen heteroatom may optionally be quaternized. Theheteroatom(s) (e.g., O, N, P, S, B, As, and Si) may be placed at anyinterior position of the heteroalkyl group or at the position at whichthe alkyl group is attached to the remainder of the molecule.Heteroalkyl is an uncyclized chain. Examples include, but are notlimited to: —CH₂—CH₂—O—CH₃, —CH₂—CH₂—NH—CH₃, —CH₂—CH₂—N(CH₃)—CH₃,—CH₂—S—CH₂—CH₃, —CH₂—CH₂—S(O)—CH₃, —CH₂—CH₂—S(O)₂, —CH₃, —CH═CHO—CH₃,—Si(CH₃)₃, —CH₂—CH═N—OCH₃, —CH═CH—N(CH₃)—CH₃, —O—CH₃, —O—CH₂—CH₃, and—CN. Up to two or three heteroatoms may be consecutive, such as, forexample, —CH₂—NH—OCH₃ and —CH₂—O—Si(CH₃)₃.

Similarly, the term “heteroalkylene,” by itself or as part of anothersubstituent, means, unless otherwise stated, a divalent radical derivedfrom heteroalkyl, as exemplified, but not limited by,—CH₂—CH₂—S—CH₂—CH₂— and —CH₂—S—CH₂—CH₂—NH—CH₂₋. For heteroalkylenegroups, heteroatoms can also occupy either or both of the chain termini(e.g., alkyleneoxy, alkylenedioxy, alkyleneamino, alkylenediamino, andthe like). Still further, for alkylene and heteroalkylene linkinggroups, no orientation of the linking group is implied by the directionin which the formula of the linking group is written. For example, theformula —C(O)₂R′— represents both —C(O)₂R′— and —R′C(O)₂, —. Asdescribed above, heteroalkyl groups, as used herein, include thosegroups that are attached to the remainder of the molecule through aheteroatom, such as —C(O)R′, —C(O)NR′, —NR′R″, —OR′, —SR′, and/or—SO₂R′. Where “heteroalkyl” is recited, followed by recitations ofspecific heteroalkyl groups, such as —NR′R″ or the like, it will beunderstood that the terms heteroalkyl and —NR′R″ are not redundant ormutually exclusive. Rather, the specific heteroalkyl groups are recitedto add clarity. Thus, the term “heteroalkyl” should not be interpretedherein as excluding specific heteroalkyl groups, such as —NR′R″ or thelike.

The terms “cycloalkyl” and “heterocycloalkyl,” by themselves or incombination with other terms, mean, unless otherwise stated, cyclicversions of “alkyl” and “heteroalkyl,” respectively. Cycloalkyl andheteroalkyl are not aromatic. Additionally, for heterocycloalkyl, aheteroatom can occupy the position at which the heterocycle is attachedto the remainder of the molecule. Examples of cycloalkyl include, butare not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl,1-cyclohexenyl, 3-cyclohexenyl, cycloheptyl, and the like. Examples ofheterocycloalkyl include, but are not limited to,1-(1,2,5,6-tetrahydropyridyl), 1-piperidinyl, 2-piperidinyl,3-piperidinyl, 4-morpholinyl, 3-morpholinyl, tetrahydrofuran-2-yl,tetrahydrofuran-3-yl, tetrahydrothien-2-yl, tetrahydrothien-3-yl,1-piperazinyl, 2-piperazinyl, and the like. A “cycloalkylene” and a“heterocycloalkylene,” alone or as part of another substituent, means adivalent radical derived from a cycloalkyl and heterocycloalkyl,respectively.

The terms “halo” or “halogen,” by themselves or as part of anothersubstituent, mean, unless otherwise stated, a fluorine, chlorine,bromine, or iodine atom. Additionally, terms such as “haloalkyl” aremeant to include monohaloalkyl and polyhaloalkyl. For example, the term“halo(C₁-C₄)alkyl” includes, but is not limited to, fluoromethyl,difluoromethyl, trifluoromethyl, 2,2,2-trifluoroethyl, 4-chlorobutyl,3-bromopropyl, and the like.

The term “acyl” means, unless otherwise stated, —C(O)R where R is asubstituted or unsubstituted alkyl, substituted or unsubstitutedcycloalkyl, substituted or unsubstituted heteroalkyl, substituted orunsubstituted heterocycloalkyl, substituted or unsubstituted aryl, orsubstituted or unsubstituted heteroaryl.

The term “aryl” means, unless otherwise stated, a polyunsaturated,aromatic, hydrocarbon substituent, which can be a single ring ormultiple rings (preferably from 1 to 3 rings) that are fused together(i.e., a fused ring aryl) or linked covalently. A fused ring aryl refersto multiple rings fused together wherein at least one of the fused ringsis an aryl ring. The term “heteroaryl” refers to aryl groups (or rings)that contain at least one heteroatom such as N, O, or S, wherein thenitrogen and sulfur atoms are optionally oxidized, and the nitrogenatom(s) are optionally quaternized. Thus, the term “heteroaryl” includesfused ring heteroaryl groups (i.e., multiple rings fused togetherwherein at least one of the fused rings is a heteroaromatic ring). A5.6-fused ring heteroarylene refers to two rings fused together, whereinone ring has 5 members and the other ring has 6 members, and wherein atleast one ring is a heteroaryl ring. Likewise, a 6.6-fused ringheteroarylene refers to two rings fused together, wherein one ring has 6members and the other ring has 6 members, and wherein at least one ringis a heteroaryl ring. And a 6.5-fused ring heteroarylene refers to tworings fused together, wherein one ring has 6 members and the other ringhas 5 members, and wherein at least one ring is a heteroaryl ring. Aheteroaryl group can be attached to the remainder of the moleculethrough a carbon or heteroatom. Non-limiting examples of aryl andheteroaryl groups include phenyl, naphthyl, pyrrolyl, pyrazolyl,pyridazinyl, triazinyl, pyrimidinyl, imidazolyl, pyrazinyl, purinyl,oxazolyl, isoxazolyl, thiazolyl, furyl, thienyl, pyridyl, pyrimidyl,benzothiazolyl, benzoxazoyl benzimidazolyl, benzofuran, isobenzofuranyl,indolyl, isoindolyl, benzothiophenyl, isoquinolyl, quinoxalinyl,quinolyl, 1-naphthyl, 2-naphthyl, 4-biphenyl, 1-pyrrolyl, 2-pyrrolyl,3-pyrrolyl, 3-pyrazolyl, 2-imidazolyl, 4-imidazolyl, pyrazinyl,2-oxazolyl, 4-oxazolyl, 2-phenyl-4-oxazolyl, 5-oxazolyl, 3-isoxazolyl,4-isoxazolyl, 5-isoxazolyl, 2-thiazolyl, 4-thiazolyl, 5-thiazolyl,2-furyl, 3-furyl, 2-thienyl, 3-thienyl, 2-pyridyl, 3-pyridyl, 4-pyridyl,2-pyrimidyl, 4-pyrimidyl, 5-benzothiazolyl, purinyl, 2-benzimidazolyl,5-indolyl, 1-isoquinolyl, 5-isoquinolyl, 2-quinoxalinyl, 5-quinoxalinyl,3-quinolyl, and 6-quinolyl. Substituents for each of the above notedaryl and heteroaryl ring systems are selected from the group ofacceptable substituents described below. An “arylene” and a“heteroarylene,” alone or as part of another substituent, mean adivalent radical derived from an aryl and heteroaryl, respectively. Aheteroaryl group substituent may be a —O— bonded to a ring heteroatomnitrogen.

A “fused ring aryl-heterocycloalkyl” is an aryl fused to aheterocycloalkyl. A “fused ring heteroaryl-heterocycloalkyl” is aheteroaryl fused to a heterocycloalkyl. A “fused ringheterocycloalkyl-cycloalkyl” is a heterocycloalkyl fused to acycloalkyl. A “fused ring heterocycloalkyl-heterocycloalkyl” is aheterocycloalkyl fused to another heterocycloalkyl. Fused ringaryl-heterocycloalkyl, fused ring heteroaryl-heterocycloalkyl, fusedring heterocycloalkyl-cycloalkyl, or fused ringheterocycloalkyl-heterocycloalkyl may each independently beunsubstituted or substituted with one or more of the substituentsdescribed herein. Fused ring aryl-heterocycloalkyl, fused ringheteroaryl-heterocycloalkyl, fused ring heterocycloalkyl-cycloalkyl, orfused ring heterocycloalkyl-heterocycloalkyl may each independently benamed according to the size of each of the fused rings. Thus, forexample, 6,5 aryl-heterocycloalkyl fused ring describes a 6 memberedaryl moiety fused to a 5 membered heterocycloalkyl. Spirocyclic ringsare two or more rings wherein adjacent rings are attached through asingle atom. The individual rings within spirocyclic rings may beidentical or different. Individual rings in spirocyclic rings may besubstituted or unsubstituted and may have different substituents fromother individual rings within a set of spirocyclic rings. Possiblesubstituents for individual rings within spirocyclic rings are thepossible substituents for the same ring when not part of spirocyclicrings (e.g. substituents for cycloalkyl or heterocycloalkyl rings).Spirocylic rings may be substituted or unsubstituted cycloalkyl,substituted or unsubstituted cycloalkylene, substituted or unsubstitutedheterocycloalkyl or substituted or unsubstituted heterocycloalkylene andindividual rings within a spirocyclic ring group may be any of theimmediately previous list, including having all rings of one type (e.g.all rings being substituted heterocycloalkylene wherein each ring may bethe same or different substituted heterocycloalkylene). When referringto a spirocyclic ring system, heterocyclic spirocyclic rings means aspirocyclic rings wherein at least one ring is a heterocyclic ring andwherein each ring may be a different ring. When referring to aspirocyclic ring system, substituted spirocyclic rings means that atleast one ring is substituted and each substituent may optionally bedifferent.

The term “oxo,” as used herein, means an oxygen that is double bonded toa carbon atom.

Each of the above terms (e.g., “alkyl,” “heteroalkyl,” “aryl,” and“heteroaryl”) includes both substituted and unsubstituted forms of theindicated radical. Preferred substituents for each type of radical areprovided below.

Substituents for the alkyl and heteroalkyl radicals (including thosegroups often referred to as alkylene, alkenyl, heteroalkylene,heteroalkenyl, alkynyl, cycloalkyl, heterocycloalkyl, cycloalkenyl, andheterocycloalkenyl) can be one or more of a variety of groups selectedfrom, but not limited to, —OR′, ═O, ═NR′, ═N—OR′, —NR′R″, —SR′,-halogen, —SiR′R′R′″, —OC(O)R′, —C(O)R′, —CO₂R′, —CONR′R″, —OC(O)NR′R″,—NR″C(O)R′, —NR′—C(O)NR″R′″, —NR″C(O)₂R′, —NR—C(NR′R″R′″)═NR″″,—NR—C(NR′R″)═NR′″, —S(O)R′, —S(O)₂R′, —S(O)₂NR′R″, —NRSO₂R′, —NR′NR″R′″,—ONR′R″, —NR′C═(O)NR″NR″′R″″, —CN, —NO₂, —NR′SO₂R″, —NR′C═(O)R″,—NR′C(O)—OR″, —NR′OR″, in a number ranging from zero to (2m′+1), wherem′ is the total number of carbon atoms in such radical. R, R′, R″, R′″,and R″″ each preferably independently refer to hydrogen, substituted orunsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl,substituted or unsubstituted heterocycloalkyl, substituted orunsubstituted aryl (e.g., aryl substituted with 1-3 halogens),substituted or unsubstituted heteroaryl, substituted or unsubstitutedalkyl, alkoxy, or thioalkoxy groups, or arylalkyl groups. When acompound of the invention includes more than one R group, for example,each of the R groups is independently selected as are each R′, R″, R′″,and R″″ group when more than one of these groups is present. When R′ andR″ are attached to the same nitrogen atom, they can be combined with thenitrogen atom to form a 4-, 5-, 6-, or 7-membered ring. For example,—NR′R″ includes, but is not limited to, 1-pyrrolidinyl and4-morpholinyl. From the above discussion of substituents, one of skillin the art will understand that the term “alkyl” is meant to includegroups including carbon atoms bound to groups other than hydrogengroups, such as haloalkyl (e.g., —CF₃ and —CH₂CF₃) and acyl (e.g.,—C(O)CH₃, —C(O)CF₃, —C(O)CH₂OCH₃, and the like).

Similar to the substituents described for the alkyl radical,substituents for the aryl and heteroaryl groups are varied and areselected from, for example: —OR′, —NR′R″, —SR′, -halogen, —SiR′R′R′″,—OC(O)R′, —C(O)R′, —CO₂R′, —CONR′R″, —OC(O)NR′R″, —NR″C(O)R′,—NR′—C(O)NR″R″′, —NR″C(O)₂R′, —NR—C(NR′R″R′″)═NR″″, —NR—C(NR′R″)═NR′″,—S(O)R′, —S(O)₂R′, —S(O)₂NR′R″, —NRSO₂R′, —NR′NR″R′″, —ONR′R″,—NR′C═(O)NR″NR″R″″, —CN, —NO₂, —R′, —N₃, —CH(Ph)₂, fluoro(C₁-C₄)alkoxy,and fluoro(C₁-C₄)alkyl, —NR′SO₂R″, —NR′C═(O)R″, —NR′C(O)—OR″, —NR′OR″,in a number ranging from zero to the total number of open valences onthe aromatic ring system; and where R′, R″, R′″, and R″″ are preferablyindependently selected from hydrogen, substituted or unsubstitutedalkyl, substituted or unsubstituted heteroalkyl, substituted orunsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl,substituted or unsubstituted aryl, and substituted or unsubstitutedheteroaryl. When a compound of the invention includes more than one Rgroup, for example, each of the R groups is independently selected asare each R′, R″, R′″, and R″″ groups when more than one of these groupsis present.

Substituents for rings (e.g. cycloalkyl, heterocycloalkyl, aryl,heteroaryl, cycloalkylene, heterocycloalkylene, arylene, orheteroarylene) may be depicted as substituents on the ring rather thanon a specific atom of a ring (commonly referred to as a floatingsubstituent). In such a case, the substituent may be attached to any ofthe ring atoms (obeying the rules of chemical valency) and in the caseof fused rings or spirocyclic rings, a substituent depicted asassociated with one member of the fused rings or spirocyclic rings (afloating substituent on a single ring), may be a substituent on any ofthe fused rings or spirocyclic rings (a floating substituent on multiplerings). When a substituent is attached to a ring, but not a specificatom (a floating substituent), and a subscript for the substituent is aninteger greater than one, the multiple substituents may be on the sameatom, same ring, different atoms, different fused rings, differentspirocyclic rings, and each substituent may optionally be different.Where a point of attachment of a ring to the remainder of a molecule isnot limited to a single atom (a floating substituent), the attachmentpoint may be any atom of the ring and in the case of a fused ring orspirocyclic ring, any atom of any of the fused rings or spirocyclicrings while obeying the rules of chemical valency. Where a ring, fusedrings, or spirocyclic rings contain one or more ring heteroatoms and thering, fused rings, or spirocyclic rings are shown with one more floatingsubstituents (including, but not limited to, points of attachment to theremainder of the molecule), the floating substituents may be bonded tothe heteroatoms. Where the ring heteroatoms are shown bound to one ormore hydrogens (e.g. a ring nitrogen with two bonds to ring atoms and athird bond to a hydrogen) in the structure or formula with the floatingsubstituent, when the heteroatom is bonded to the floating substituent,the substituent will be understood to replace the hydrogen, whileobeying the rules of chemical valency.

Two or more substituents may optionally be joined to form aryl,heteroaryl, cycloalkyl, or heterocycloalkyl groups. Such so-calledring-forming substituents are typically, though not necessarily, foundattached to a cyclic base structure. In one embodiment, the ring-formingsubstituents are attached to adjacent members of the base structure. Forexample, two ring-forming substituents attached to adjacent members of acyclic base structure create a fused ring structure. In anotherembodiment, the ring-forming substituents are attached to a singlemember of the base structure. For example, two ring-forming substituentsattached to a single member of a cyclic base structure create aspirocyclic structure. In yet another embodiment, the ring-formingsubstituents are attached to non-adjacent members of the base structure.

Two of the substituents on adjacent atoms of the aryl or heteroaryl ringmay optionally form a ring of the formula -T-C(O)—(CRR′)_(q)—U—, whereinT and U are independently —NR—, —O—, —CRR′—, or a single bond, and q isan integer of from 0 to 3. Alternatively, two of the substituents onadjacent atoms of the aryl or heteroaryl ring may optionally be replacedwith a substituent of the formula -A-(CH₂)_(r), —B—, wherein A and B areindependently —CRR′—, —O—, —NR—, —S—, —S(O)—, —S(O)₂—, —S(O)₂NR′—, or asingle bond, and r is an integer of from 1 to 4. One of the single bondsof the new ring so formed may optionally be replaced with a double bond.Alternatively, two of the substituents on adjacent atoms of the aryl orheteroaryl ring may optionally be replaced with a substituent of theformula —(CRR′)_(s), —X′— (C″R″R″′)_(d), —, where s and d areindependently integers of from 0 to 3, and X′ is —O—, —NR′—, —S—,—S(O)—, —S(O)₂—, or —S(O)₂NR′—. The substituents R, R′, R″, and R′″ arepreferably independently selected from hydrogen, substituted orunsubstituted alkyl, substituted or unsubstituted heteroalkyl,substituted or unsubstituted cycloalkyl, substituted or unsubstitutedheterocycloalkyl, substituted or unsubstituted aryl, and substituted orunsubstituted heteroaryl.

As used herein, the terms “heteroatom” or “ring heteroatom” are meant toinclude, oxygen (O), nitrogen (N), sulfur (S), phosphorus (P), Boron(B), Arsenic (As), and silicon (Si).

A “substituent group,” as used herein, means a group selected from thefollowing moieties:

(A) oxo, halogen, —CF₃, —CN, —OH, —NH₂, —COOH, —CONH₂, —NO₂, —SH,—SO₂Cl, —SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂, —ONH₂, —NHC═(O)NHNH₂,—NHC═(O)NH₂, —NHSO₂H, —NHC═(O)H, —NHC(O)—OH, —NHOH, —OCF₃, —OCHF₂,unsubstituted alkyl, unsubstituted heteroalkyl, unsubstitutedcycloalkyl, unsubstituted heterocycloalkyl, unsubstituted aryl,unsubstituted heteroaryl, and(B) alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, andheteroaryl, substituted with at least one substituent selected from:(i) oxo, halogen, —CF₃, —CN, —OH, —NH₂, —COOH, —CONH₂, —NO₂, —SH,—SO₂Cl, —SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂, —ONH₂, —NHC═(O)NHNH₂,—NHC═(O)NH₂, —NHSO₂H, —NHC═(O)H, —NHC(O)—OH, —NHOH, —OCF₃, —OCHF₂,unsubstituted alkyl, unsubstituted heteroalkyl, unsubstitutedcycloalkyl, unsubstituted heterocycloalkyl, unsubstituted aryl,unsubstituted heteroaryl, and(ii) alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, andheteroaryl, substituted with at least one substituent selected from:(a) oxo, halogen, —CF₃, —CN, —OH, —NH₂, —COOH, —CONH₂, —NO₂, —SH,—SO₂Cl, —SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂, —ONH₂, —NHC═(O)NHNH₂,—NHC═(O)NH₂, —NHSO₂H, —NHC═(O)H, —NHC(O)—OH, —NHOH, —OCF₃, —OCHF₂,unsubstituted alkyl, unsubstituted heteroalkyl, unsubstitutedcycloalkyl, unsubstituted heterocycloalkyl, unsubstituted aryl,unsubstituted heteroaryl, and(b) alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, orheteroaryl, substituted with at least one substituent selected from:oxo, halogen, —CF₃, —CN, —OH, —NH₂, —COOH, —CONH₂, —NO₂, —SH, —SO₂Cl,—SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂, —ONH₂, —NHC═(O)NHNH₂, —NHC═(O)NH₂,—NHSO₂H, —NHC═(O)H, —NHC(O)—OH, —NHOH, —OCF₃, —OCHF₂, unsubstitutedalkyl, unsubstituted heteroalkyl, unsubstituted cycloalkyl,unsubstituted heterocycloalkyl, unsubstituted aryl, and unsubstitutedheteroaryl.

A “size-limited substituent” or “size-limited substituent group,” asused herein, means a group selected from all of the substituentsdescribed above for a “substituent group,” wherein each substituted orunsubstituted alkyl is a substituted or unsubstituted C₁-C₂₀ alkyl, eachsubstituted or unsubstituted heteroalkyl is a substituted orunsubstituted 2 to 20 membered heteroalkyl, each substituted orunsubstituted cycloalkyl is a substituted or unsubstituted C₃-C₈cycloalkyl, each substituted or unsubstituted heterocycloalkyl is asubstituted or unsubstituted 3 to 8 membered heterocycloalkyl, eachsubstituted or unsubstituted aryl is a substituted or unsubstitutedC₆-C₁₀ aryl, and each substituted or unsubstituted heteroaryl is asubstituted or unsubstituted 5 to 10 membered heteroaryl.

A “lower substituent” or “lower substituent group,” as used herein,means a group selected from all of the substituents described above fora “substituent group,” wherein each substituted or unsubstituted alkylis a substituted or unsubstituted C₁-C₈ alkyl, each substituted orunsubstituted heteroalkyl is a substituted or unsubstituted 2 to 8membered heteroalkyl, each substituted or unsubstituted cycloalkyl is asubstituted or unsubstituted C₃-C₇ cycloalkyl, each substituted orunsubstituted heterocycloalkyl is a substituted or unsubstituted 3 to 7membered heterocycloalkyl, each substituted or unsubstituted aryl is asubstituted or unsubstituted C₆-C₁₀ aryl, and each substituted orunsubstituted heteroaryl is a substituted or unsubstituted 5 to 9membered heteroaryl.

In some embodiments, each substituted group described in the compoundsherein is substituted with at least one substituent group. Morespecifically, in some embodiments, each substituted alkyl, substitutedheteroalkyl, substituted cycloalkyl, substituted heterocycloalkyl,substituted aryl, substituted heteroaryl, substituted alkylene,substituted heteroalkylene, substituted cycloalkylene, substitutedheterocycloalkylene, substituted arylene, and/or substitutedheteroarylene described in the compounds herein are substituted with atleast one substituent group. In other embodiments, at least one or allof these groups are substituted with at least one size-limitedsubstituent group. In other embodiments, at least one or all of thesegroups are substituted with at least one lower substituent group.

In other embodiments of the compounds herein, each substituted orunsubstituted alkyl may be a substituted or unsubstituted C₁-C₂₀ alkyl,each substituted or unsubstituted heteroalkyl is a substituted orunsubstituted 2 to 20 membered heteroalkyl, each substituted orunsubstituted cycloalkyl is a substituted or unsubstituted C₃-C₈cycloalkyl, each substituted or unsubstituted heterocycloalkyl is asubstituted or unsubstituted 3 to 8 membered heterocycloalkyl, eachsubstituted or unsubstituted aryl is a substituted or unsubstitutedC₆-C₁₀ aryl, and/or each substituted or unsubstituted heteroaryl is asubstituted or unsubstituted 5 to 10 membered heteroaryl. In someembodiments of the compounds herein, each substituted or unsubstitutedalkylene is a substituted or unsubstituted C₁-C₂₀ alkylene, eachsubstituted or unsubstituted heteroalkylene is a substituted orunsubstituted 2 to 20 membered heteroalkylene, each substituted orunsubstituted cycloalkylene is a substituted or unsubstituted C₃-C₈cycloalkylene, each substituted or unsubstituted heterocycloalkylene isa substituted or unsubstituted 3 to 8 membered heterocycloalkylene, eachsubstituted or unsubstituted arylene is a substituted or unsubstitutedC₆-C₁₀ arylene, and/or each substituted or unsubstituted heteroaryleneis a substituted or unsubstituted 5 to 10 membered heteroarylene.

In some embodiments, each substituted or unsubstituted alkyl is asubstituted or unsubstituted C₁-C₈ alkyl, each substituted orunsubstituted heteroalkyl is a substituted or unsubstituted 2 to 8membered heteroalkyl, each substituted or unsubstituted cycloalkyl is asubstituted or unsubstituted C₃-C₇ cycloalkyl, each substituted orunsubstituted heterocycloalkyl is a substituted or unsubstituted 3 to 7membered heterocycloalkyl, each substituted or unsubstituted aryl is asubstituted or unsubstituted C₆-C₁₀ aryl, and/or each substituted orunsubstituted heteroaryl is a substituted or unsubstituted 5 to 9membered heteroaryl. In some embodiments, each substituted orunsubstituted alkylene is a substituted or unsubstituted C₁-C₈ alkylene,each substituted or unsubstituted heteroalkylene is a substituted orunsubstituted 2 to 8 membered heteroalkylene, each substituted orunsubstituted cycloalkylene is a substituted or unsubstituted C₃-C₇cycloalkylene, each substituted or unsubstituted heterocycloalkylene isa substituted or unsubstituted 3 to 7 membered heterocycloalkylene, eachsubstituted or unsubstituted arylene is a substituted or unsubstitutedC₆-C₁₀ arylene, and/or each substituted or unsubstituted heteroaryleneis a substituted or unsubstituted 5 to 9 membered heteroarylene. In someembodiments, the compound is a chemical species set forth in theExamples section, figures, or tables below.

Certain compounds described herein possess asymmetric carbon atoms(optical or chiral centers) or double bonds; the enantiomers, racemates,diastereomers, tautomers, geometric isomers, stereoisometric forms thatmay be defined, in terms of absolute stereochemistry, as (R)- or (S)-or, as (D)- or (L)- for amino acids, and individual isomers areencompassed within the scope of the present invention. The compounds ofthe present invention do not include those which are known in art to betoo unstable to synthesize and/or isolate. The present invention ismeant to include compounds in racemic and optically pure forms.Optically active (R)- and (S)-, or (D)- and (L)-isomers may be preparedusing chiral synthons or chiral reagents, or resolved using conventionaltechniques. When the compounds described herein contain olefinic bondsor other centers of geometric asymmetry, and unless specified otherwise,it is intended that the compounds include both E and Z geometricisomers.

As used herein, the term “isomers” refers to compounds having the samenumber and kind of atoms, and hence the same molecular weight, butdiffering in respect to the structural arrangement or configuration ofthe atoms.

The term “tautomer,” as used herein, refers to one of two or morestructural isomers which exist in equilibrium and which are readilyconverted from one isomeric form to another.

It will be apparent to one skilled in the art that certain compounds ofthis invention may exist in tautomeric forms, all such tautomeric formsof the compounds being within the scope of the invention.

Unless otherwise stated, structures depicted herein are also meant toinclude all stereochemical forms of the structure; i.e., the (R) and (S)configurations for each asymmetric center. Therefore, singlestereochemical isomers as well as enantiomeric and diastereomericmixtures of the present compounds, generally recognized as stable bythose skilled in the art, are within the scope of the invention.

Unless otherwise stated, structures depicted herein are also meant toinclude compounds which differ only in the presence of one or moreisotopically enriched atoms. For example, compounds having the presentstructures except for the replacement of a hydrogen by a deuterium ortritium, replacement of fluoride by ¹⁸F, or the replacement of a carbonby ¹³C- or ¹⁴C-enriched carbon are within the scope of this invention.

The compounds of the present invention may also contain unnaturalproportions of atomic isotopes at one or more of the atoms thatconstitute such compounds. For example, the compounds may beradiolabeled with radioactive isotopes, such as for example tritium(³H), fluroide (¹⁸F), iodine-125 (¹²⁵I), or carbon-14 (¹⁴C). Allisotopic variations of the compounds of the present invention, whetherradioactive or not, are encompassed within the scope of the presentinvention.

The symbol “

” denotes the point of attachment of a chemical moiety to the remainderof a molecule or chemical formula.

Where a moiety is substituted with an R substituent, the group may bereferred to as “R-substituted.” Where a moiety is R-substituted, themoiety is substituted with at least one R substituent and each Rsubstituent is optionally different. Where a particular R group ispresent in the description of a chemical genus (such as Formula (I)), aRoman decimal symbol may be used to distinguish each appearance of thatparticular R group. For example, where multiple R¹³ substituents arepresent, each R¹³ substituent may be distinguished as R^(13.1),R^(13.2), R^(13.3), R^(13.4), etc., wherein each of R^(13.1), R^(13.2),R^(13.3), R^(13.4), etc. is defined within the scope of the definitionof R¹³ and optionally differently. The terms “a” or “an,” as used inherein means one or more. In addition, the phrase “substituted witha[n],” as used herein, means the specified group may be substituted withone or more of any or all of the named substituents. For example, wherea group, such as an alkyl or heteroaryl group, is “substituted with anunsubstituted C₁-C₂₀ alkyl, or unsubstituted 2 to 20 memberedheteroalkyl,” the group may contain one or more unsubstituted C₁-C₂₀alkyls, and/or one or more unsubstituted 2 to 20 membered heteroalkyls.

Description of compounds of the present invention is limited byprinciples of chemical bonding known to those skilled in the art.Accordingly, where a group may be substituted by one or more of a numberof substituents, such substitutions are selected so as to comply withprinciples of chemical bonding and to give compounds which are notinherently unstable and/or would be known to one of ordinary skill inthe art as likely to be unstable under ambient conditions, such asaqueous, neutral, and several known physiological conditions. Forexample, a heterocycloalkyl or heteroaryl is attached to the remainderof the molecule via a ring heteroatom in compliance with principles ofchemical bonding known to those skilled in the art thereby avoidinginherently unstable compounds.

“Analog,” or “analogue” are used in accordance with plain ordinarymeaning within Chemistry and Biology and refer to a chemical compoundthat is structurally similar to another compound (i.e., a so-called“reference” compound) but differs in composition, e.g., in thereplacement of one atom by an atom of a different element, or in thepresence of a particular functional group, or the replacement of onefunctional group by another functional group, or the absolutestereochemistry of one or more chiral centers of the reference compound.Accordingly, an analogue is a compound that is similar or comparable infunction and appearance but not in structure or origin to a referencecompound.

The terms “cystic fibrosis transmembrane conductance regulator,” and“CFTR” are here used interchangeably and according to their common,ordinary meaning and refer to proteins of the same or similar names andfunctional fragments and homologs thereof. The term includes anyrecombinant or naturally occurring form of, or variants thereof thatmaintain CFTR activity (e.g. within at least 30%, 40%, 50%, 60%, 70%,80%, 90%, 95%, or 100% activity compared to CFTR).

The term “pharmaceutically acceptable salts” is meant to include saltsof the active compounds that are prepared with relatively nontoxic acidsor bases, depending on the particular substituents found on thecompounds described herein. When compounds of the present inventioncontain relatively acidic functionalities, base addition salts can beobtained by contacting the neutral form of such compounds with asufficient amount of the desired base, either neat or in a suitableinert solvent. Examples of pharmaceutically acceptable base additionsalts include sodium, potassium, calcium, ammonium, organic amino, ormagnesium salt, or a similar salt. When compounds of the presentinvention contain relatively basic functionalities, acid addition saltscan be obtained by contacting the neutral form of such compounds with asufficient amount of the desired acid, either neat or in a suitableinert solvent. Examples of pharmaceutically acceptable acid additionsalts include those derived from inorganic acids like hydrochloric,hydrobromic, nitric, carbonic, monohydrogencarbonic, phosphoric,monohydrogenphosphoric, dihydrogenphosphoric, sulfuric,monohydrogensulfuric, hydriodic, or phosphorous acids and the like, aswell as the salts derived from relatively nontoxic organic acids likeacetic, propionic, isobutyric, maleic, malonic, benzoic, succinic,suberic, fumaric, lactic, mandelic, phthalic, benzenesulfonic,p-tolylsulfonic, citric, tartaric, oxalic, methanesulfonic, and thelike. Also included are salts of amino acids such as arginate and thelike, and salts of organic acids like glucuronic or galactunoric acidsand the like (see, for example, Berge et al., “Pharmaceutical Salts”,Journal of Pharmaceutical Science, 1977, 66, 1-19). Certain specificcompounds of the present invention contain both basic and acidicfunctionalities that allow the compounds to be converted into eitherbase or acid addition salts.

Thus, the compounds of the present invention may exist as salts, such aswith pharmaceutically acceptable acids. The present invention includessuch salts. Examples of such salts include hydrochlorides,hydrobromides, sulfates, methanesulfonates, nitrates, maleates,acetates, citrates, fumarates, tartrates (e.g., (+)-tartrates,(−)-tartrates, or mixtures thereof including racemic mixtures),succinates, benzoates, and salts with amino acids such as glutamic acid.These salts may be prepared by methods known to those skilled in theart.

The neutral forms of the compounds are preferably regenerated bycontacting the salt with a base or acid and isolating the parentcompound in the conventional manner. The parent form of the compounddiffers from the various salt forms in certain physical properties, suchas solubility in polar solvents.

In addition to salt forms, the present invention provides compounds,which are in a prodrug form. Prodrugs of the compounds described hereininclude those compounds that readily undergo chemical or enzymaticchanges under physiological conditions to provide the compounds of thepresent invention. Additionally, prodrugs can be converted to thecompounds of the present invention by chemical or biochemical methods inan ex vivo environment. For example, prodrugs can be slowly converted tothe compounds of the present invention when placed in a transdermalpatch reservoir with a suitable enzyme or chemical reagent.

Certain compounds of the present invention can exist in unsolvated formsas well as solvated forms, including hydrated forms. In general, thesolvated forms are equivalent to unsolvated forms and are encompassedwithin the scope of the present invention. Certain compounds of thepresent invention may exist in multiple crystalline or amorphous forms.In general, all physical forms are equivalent for the uses contemplatedby the present invention and are intended to be within the scope of thepresent invention.

As used herein, the term “salt” refers to acid or base salts of thecompounds used in the methods of the present invention. Illustrativeexamples of acceptable salts are mineral acid (hydrochloric acid,hydrobromic acid, phosphoric acid, and the like) salts, organic acid(acetic acid, propionic acid, glutamic acid, citric acid and the like)salts, quaternary ammonium (methyl iodide, ethyl iodide, and the like)salts.

The terms “treating”, or “treatment” refer to any indicia of success inthe treatment or amelioration of an injury, disease, pathology orcondition, including any objective or subjective parameter such asabatement; remission; diminishing of symptoms or making the injury,pathology or condition more tolerable to the patient; slowing in therate of degeneration or decline; making the final point of degenerationless debilitating; or improving a patient's physical or mentalwell-being. The treatment or amelioration of symptoms can be based onobjective or subjective parameters, including the results of a physicalexamination, neuropsychiatric exams, and/or a psychiatric evaluation.The term “treating” and conjugations thereof, include prevention of aninjury, pathology, condition, or disease.

An “effective amount” is an amount sufficient to accomplish a statedpurpose (e.g. achieve the effect for which it is administered, treat adisease, reduce enzyme activity, increase enzyme activity, reduce one ormore symptoms of a disease or condition). An example of an “effectiveamount” is an amount sufficient to contribute to the treatment,prevention, or reduction of a symptom or symptoms of a disease, whichcould also be referred to as a “therapeutically effective amount.” A“reduction” of a symptom or symptoms (and grammatical equivalents ofthis phrase) means decreasing of the severity or frequency of thesymptom(s), or elimination of the symptom(s). A “prophylacticallyeffective amount” of a drug is an amount of a drug that, whenadministered to a subject, will have the intended prophylactic effect,e.g., preventing or delaying the onset (or reoccurrence) of an injury,disease, pathology or condition, or reducing the likelihood of the onset(or reoccurrence) of an injury, disease, pathology, or condition, ortheir symptoms. The full prophylactic effect does not necessarily occurby administration of one dose, and may occur only after administrationof a series of doses. Thus, a prophylactically effective amount may beadministered in one or more administrations. The exact amounts willdepend on the purpose of the treatment, and will be ascertainable by oneskilled in the art using known techniques (see, e.g., Lieberman,Pharmaceutical Dosage Forms (vols. 1-3, 1992); Lloyd, The Art, Scienceand Technology of Pharmaceutical Compounding (1999); Pickar, DosageCalculations (1999); and Remington: The Science and Practice ofPharmacy, 20th Edition, 2003, Gennaro, Ed., Lippincott, Williams &Wilkins).

For any compound described herein, the therapeutically effective amountcan be initially determined from cell culture assays. Targetconcentrations will be those concentrations of active compound(s) thatare capable of achieving the methods described herein, as measured usingthe methods described herein or known in the art.

As is well known in the art, therapeutically effective amounts for usein humans can also be determined from animal models. For example, a dosefor humans can be formulated to achieve a concentration that has beenfound to be effective in animals. The dosage in humans can be adjustedby monitoring compounds effectiveness and adjusting the dosage upwardsor downwards, as described above. Adjusting the dose to achieve maximalefficacy in humans based on the methods described above and othermethods is well within the capabilities of the ordinarily skilledartisan.

Dosages may be varied depending upon the requirements of the patient andthe compound being employed. The dose administered to a patient, in thecontext of the present invention should be sufficient to effect abeneficial therapeutic response in the patient over time. The size ofthe dose also will be determined by the existence, nature, and extent ofany adverse side-effects. Determination of the proper dosage for aparticular situation is within the skill of the practitioner. Generally,treatment is initiated with smaller dosages which are less than theoptimum dose of the compound. Thereafter, the dosage is increased bysmall increments until the optimum effect under circumstances isreached.

Dosage amounts and intervals can be adjusted individually to providelevels of the administered compound effective for the particularclinical indication being treated. This will provide a therapeuticregimen that is commensurate with the severity of the individual'sdisease state.

Utilizing the teachings provided herein, an effective prophylactic ortherapeutic treatment regimen can be planned that does not causesubstantial toxicity and yet is effective to treat the clinical symptomsdemonstrated by the particular patient. This planning should involve thecareful choice of active compound by considering factors such ascompound potency, relative bioavailability, patient body weight,presence and severity of adverse side effects, preferred mode ofadministration and the toxicity profile of the selected agent.

“Control” or “control experiment” is used in accordance with its plainordinary meaning and refers to an experiment in which the subjects orreagents of the experiment are treated as in a parallel experimentexcept for omission of a procedure, reagent, or variable of theexperiment. In some instances, the control is used as a standard ofcomparison in evaluating experimental effects. In embodiments, a controlis the measurement of the activity of a protein in the absence of acompound as described herein (including embodiments and examples).

“Contacting” is used in accordance with its plain ordinary meaning andrefers to the process of allowing at least two distinct species (e.g.chemical compounds including biomolecules or cells) to becomesufficiently proximal to react, interact or physically touch. It shouldbe appreciated; however, the resulting reaction product can be produceddirectly from a reaction between the added reagents or from anintermediate from one or more of the added reagents which can beproduced in the reaction mixture.

The term “contacting” may include allowing two species to react,interact, or physically touch, wherein the two species may be a compoundas described herein and a protein or enzyme. Contacting may includeallowing a compound described herein to interact with a protein orenzyme that is involved in a signaling pathway.

As defined herein, the term “activation,” “activate,” “activating” andthe like in reference to a protein-activator interaction meanspositively affecting (e.g. increasing) the activity or function of theprotein relative to the activity or function of the protein in theabsence of the activator. Activation may refer to reduction of a diseaseor symptoms of disease. Activation may refer to an increase in theactivity of a particular protein or nucleic acid target. The protein maybe cystic fibrosis transmembrane conductance regulator. Thus, activationincludes, at least in part, partially or totally increasing stimulation,increasing, promoting, or expediting activation, or activating,sensitizing, or up-regulating signal transduction or enzymatic activityor the amount of a protein.

The term “modulator” refers to a composition that increases or decreasesthe level of a target molecule or the function of a target molecule orthe physical state of the target of the molecule.

The term “modulate” is used in accordance with its plain ordinarymeaning and refers to the act of changing or varying one or moreproperties. “Modulation” refers to the process of changing or varyingone or more properties. For example, a modulator of a target proteinchanges by increasing or decreasing a property or function of the targetmolecule or the amount of the target molecule. A modulator of a diseasedecreases a symptom, cause, or characteristic of the targeted disease.

“Selective” or “selectivity” or the like of a compound refers to thecompound's ability to discriminate between molecular targets.“Specific”, “specifically”, “specificity”, or the like of a compoundrefers to the compound's ability to cause a particular action, such asinhibition, to a particular molecular target with minimal or no actionto other proteins in the cell.

“Pharmaceutically acceptable excipient” and “pharmaceutically acceptablecarrier” refer to a substance that aids the administration of an activeagent to and absorption by a subject and can be included in thecompositions of the present invention without causing a significantadverse toxicological effect on the patient. Non-limiting examples ofpharmaceutically acceptable excipients include water, NaCl, normalsaline solutions, lactated Ringer's, normal sucrose, normal glucose,binders, fillers, disintegrants, lubricants, coatings, sweeteners,flavors, salt solutions (such as Ringer's solution), alcohols, oils,gelatins, carbohydrates such as lactose, amylose or starch, fatty acidesters, hydroxymethycellulose, polyvinyl pyrrolidine, and colors, andthe like. Such preparations can be sterilized and, if desired, mixedwith auxiliary agents such as lubricants, preservatives, stabilizers,wetting agents, emulsifiers, salts for influencing osmotic pressure,buffers, coloring, and/or aromatic substances and the like that do notdeleteriously react with the compounds of the invention. One of skill inthe art will recognize that other pharmaceutical excipients are usefulin the present invention.

The term “preparation” is intended to include the formulation of theactive compound with encapsulating material as a carrier providing acapsule in which the active component with or without other carriers, issurrounded by a carrier, which is thus in association with it.Similarly, cachets and lozenges are included. Tablets, powders,capsules, pills, cachets, and lozenges can be used as solid dosage formssuitable for oral administration.

As used herein, the term “administering” means oral administration,administration as a suppository, topical contact, intravenous,parenteral, intraperitoneal, intramuscular, intralesional, intrathecal,intranasal or subcutaneous administration, or the implantation of aslow-release device, e.g., a mini-osmotic pump, to a subject.Administration is by any route, including parenteral and transmucosal(e.g., buccal, sublingual, palatal, gingival, nasal, vaginal, rectal, ortransdermal). Parenteral administration includes, e.g., intravenous,intramuscular, intra-arteriole, intradermal, subcutaneous,intraperitoneal, intraventricular, and intracranial. Other modes ofdelivery include, but are not limited to, the use of liposomalformulations, intravenous infusion, transdermal patches, etc.

The compositions disclosed herein can be delivered by transdermally, bya topical route, formulated as applicator sticks, solutions,suspensions, emulsions, gels, creams, ointments, pastes, jellies,paints, powders, and aerosols. Oral preparations include tablets, pills,powder, dragees, capsules, liquids, lozenges, cachets, gels, syrups,slurries, suspensions, etc., suitable for ingestion by the patient.Solid form preparations include powders, tablets, pills, capsules,cachets, suppositories, and dispersible granules. Liquid formpreparations include solutions, suspensions, and emulsions, for example,water or water/propylene glycol solutions. The compositions of thepresent invention may additionally include components to providesustained release and/or comfort. Such components include high molecularweight, anionic mucomimetic polymers, gelling polysaccharides andfinely-divided drug carrier substrates. These components are discussedin greater detail in U.S. Pat. Nos. 4,911,920; 5,403,841; 5,212,162; and4,861,760. The entire contents of these patents are incorporated hereinby reference in their entirety for all purposes. The compositionsdisclosed herein can also be delivered as microspheres for slow releasein the body. For example, microspheres can be administered viaintradermal injection of drug-containing microspheres, which slowlyrelease subcutaneously (see Rao, J. Biomater Sci. Polym. Ed. 7:623-645,1995; as biodegradable and injectable gel formulations (see, e.g., GaoPharm. Res. 12:857-863, 1995); or, as microspheres for oraladministration (see, e.g., Eyles, J. Pharm. Pharmacol. 49:669-674,1997). In another embodiment, the formulations of the compositions ofthe present invention can be delivered by the use of liposomes whichfuse with the cellular membrane or are endocytosed, i.e., by employingreceptor ligands attached to the liposome, that bind to surface membraneprotein receptors of the cell resulting in endocytosis. By usingliposomes, particularly where the liposome surface carries receptorligands specific for target cells, or are otherwise preferentiallydirected to a specific organ, one can focus the delivery of thecompositions of the present invention into the target cells in vivo.(See, e.g., Al-Muhammed, J. Microencapsul. 13:293-306, 1996; Chonn,Curr. Opin. Biotechnol. 6:698-708, 1995; Ostro, Am. J. Hosp. Pharm.46:1576-1587, 1989). The compositions can also be delivered asnanoparticles.

Pharmaceutical compositions may include compositions wherein the activeingredient (e.g. compounds described herein, including embodiments orexamples) is contained in a therapeutically effective amount, i.e., inan amount effective to achieve its intended purpose. The actual amounteffective for a particular application will depend, inter alia, on thecondition being treated. When administered in methods to treat adisease, such compositions will contain an amount of active ingredienteffective to achieve the desired result, e.g., modulating the activityof a target molecule, and/or reducing, eliminating, or slowing theprogression of disease symptoms.

The dosage and frequency (single or multiple doses) administered to amammal can vary depending upon a variety of factors, for example,whether the mammal suffers from another disease, and its route ofadministration; size, age, sex, health, body weight, body mass index,and diet of the recipient; nature and extent of symptoms of the diseasebeing treated, kind of concurrent treatment, complications from thedisease being treated or other health-related problems. Othertherapeutic regimens or agents can be used in conjunction with themethods and compounds of Applicants' invention. Adjustment andmanipulation of established dosages (e.g., frequency and duration) arewell within the ability of those skilled in the art.

The compounds described herein can be used in combination with oneanother, with other active drugs known to be useful in treating adisease (e.g. anticonstipation, anti-dry eye, anti-pulmonary disease ordisorder, or anti-liver disease) or with adjunctive agents that may notbe effective alone, but may contribute to the efficacy of the activeagent. Thus, the compounds described herein may be co-administered withone another or with other active drugs known to be useful in treating adisease.

By “co-administer” it is meant that a compound described herein isadministered at the same time, just prior to, or just after theadministration of one or more additional therapies, for example, ananti-constipation or anti-dry eye agent as described herein. Thecompounds described herein can be administered alone or can beco-administered to the patient. Co-administration is meant to includesimultaneous or sequential administration of the compound individuallyor in combination (more than one compound or agent). Thus, thepreparations can also be combined, when desired, with other activesubstances (e.g. anti-constipation or anti-dry eye agents).

Co-administration includes administering one active agent (e.g. acomplex described herein) within 0.5, 1, 2, 4, 6, 8, 10, 12, 16, 20, or24 hours of a second active agent (e.g. anti-constipation or anti-dryeye agents). Also contemplated herein, are embodiments, whereco-administration includes administering one active agent within 0.5, 1,2, 4, 6, 8, 10, 12, 16, 20, or 24 hours of a second active agent.Co-administration includes administering two active agentssimultaneously, approximately simultaneously (e.g., within about 1, 5,10, 15, 20, or 30 minutes of each other), or sequentially in any order.Co-administration can be accomplished by co-formulation, i.e., preparinga single pharmaceutical composition including both active agents. Inother embodiments, the active agents can be formulated separately. Theactive and/or adjunctive agents may be linked or conjugated to oneanother. The compounds described herein may be combined with treatmentsfor constipation and dry eye disorders.

The term “associated” or “associated with” in the context of a substanceor substance activity or function associated with a disease means thatthe disease is caused by (in whole or in part), a symptom of the diseaseis caused by (in whole or in part) the substance or substance activityor function, or a side-effect of the compound (e.g. toxicity) is causedby (in whole or in part) the substance or substance activity orfunction.

“Patient,” “subject,” “patient in need thereof,” and “subject in needthereof” are herein used interchangeably and refer to a living organismsuffering from or prone to a disease or condition that can be treated byadministration of a pharmaceutical composition as provided herein.Non-limiting examples include humans, other mammals, bovines, rats,mice, dogs, monkeys, goat, sheep, cows, deer, and other non-mammaliananimals. In some embodiments, a patient is human.

“Disease” or “condition” refer to a state of being or health status of apatient or subject capable of being treated with the compounds ormethods provided herein. Disease as used herein may refer toconstipation or dry eye disorders.

Examples of anti-constipation agents include, but are not limited todiphenylmethanes, Lactobacillus paracasei, linaclotide and lubiprostone.Examples of anti-dry eye agents include, but are not limited to, topicalcyclosporine, P321 (an ENaC inhibitor) and Diquafosol.

I. Compositions

Provided herein are compounds having the formula:

Ar is substituted or unsubstituted aryl or substituted or unsubstitutedheteroaryl. L¹ and L² are independently substituted or unsubstituted(e.g. C₁-C₁₀, C₁-C₅, or C₁-C₃) alkylene. R¹ is hydrogen, halogen,—CX^(1.1) ₃, —CHX^(1.1) ₂, —CH₂X^(1.1), —CN, —SO_(n1)R^(1A),—SO_(v1)NR^(1B)R^(1C), —NHNR^(1B)R^(1C), —ONR^(1B)R^(1C),—NHC(O)NHNR^(1B)R^(1C), —NHC(O)NR^(1B)R^(1C), —N(O)_(m1),—NR^(1B)R^(1C), —C(O)R^(1D), —C(O)OR^(1D), —C(O)NR^(1B)R^(1C), —OR^(1A),—NR^(1B)SO₂R^(1A), —NR^(1B)C(O)R^(1D), —NR^(1B)C(O)OR^(1D),—NR^(1B)OR^(1D), —OCX^(1.1) ₃, —OCHX^(1.1) ₂, substituted orunsubstituted alkyl, substituted or unsubstituted heteroalkyl,substituted or unsubstituted cycloalkyl, substituted or unsubstitutedheterocycloalkyl, substituted or unsubstituted aryl, or substituted orunsubstituted heteroaryl. R² is hydrogen, halogen, —CX^(2.1) ₃,—CHX^(2.1) ₂, —CH₂X^(2.1), —CN, —SO_(n2)R^(2A), —SO_(v2)NR^(2B)R^(2C),—NHNR^(2B)R^(2C), —ONR^(2B)R^(2C), —NHC(O)NHNR^(2B)R^(2C),—NHC(O)NR^(2B)R^(2C), —N(O)_(m2), —NR^(2B)R^(2C), —C(O)R^(2D),—C(O)OR^(2D), —C(O)NR^(2B)R^(2C), —OR^(2A), —NR^(2B)SO₂R^(2A),—NR^(2B)C(O)R^(2D), BC(O)OR^(2D), —NR^(2B)OR^(2D), —OCX^(2.1) ₃,—OCHX^(2.1) ₂, substituted or unsubstituted alkyl, substituted orunsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl,substituted or unsubstituted heterocycloalkyl, substituted orunsubstituted aryl, or substituted or unsubstituted heteroaryl. R³ ishydrogen, halogen, —CX^(3.1) ₃, —CHX^(3.1) ₂, —CH₂X^(3.1), —CN,—SO_(n3)R^(3A), —SO_(v3)NR^(3B)R^(3C), —NHNR^(3B)R^(3C),—ONR^(3B)R^(3C), —NHC(O)NHNR^(3B)R^(3C), —NHC(O)NR^(3B)R^(3C),—N(O)_(m3), —NR^(3B)R^(3C), —C(O)R^(3D), —C(O)OR^(3D),—C(O)NR^(3B)R^(3C), —OR^(3A), —NR^(3B)SO₂R^(3A), —NR^(3B)C(O)R^(3D),—NR^(3B)C(O)OR^(3D), —NR^(3B)OR^(3D), —OCX^(3.1) ₃, —OCHX^(3.1) ₂,substituted or unsubstituted alkyl, substituted or unsubstitutedheteroalkyl, substituted or unsubstituted cycloalkyl, substituted orunsubstituted heterocycloalkyl, substituted or unsubstituted aryl, orsubstituted or unsubstituted heteroaryl. R⁴ is hydrogen, halogen,—CX^(4.1) ₃, —CHX^(4.1) ₂, —CH₂X^(4.1), —CN, —SO_(n4)R^(4A),—SO_(v4)NR^(4B)R^(4C), —NHNR^(4B)R^(4C), —ONR^(4B)R^(4C),—NHC(O)NHNR^(4B)R^(4C), —NHC(O)NR^(4B)R^(4C), —N(O)_(m4),—NR^(4B)R^(4C), —C(O)R^(4D), —C(O)OR^(4D), —C(O)NR^(4B)R^(4C), —OR^(4A),—NR^(4B)SO₂R^(4A), —NR^(4B)C(O)R^(4D), —NR^(4B)C(O)OR^(4D),—NR^(4B)OR^(4D), —OCX^(4.1) ₃, —OCHX^(4.1) ₂, substituted orunsubstituted alkyl, substituted or unsubstituted heteroalkyl,substituted or unsubstituted cycloalkyl, substituted or unsubstitutedheterocycloalkyl, substituted or unsubstituted aryl, or substituted orunsubstituted heteroaryl. R⁵ is hydrogen, halogen, —CX^(5.1) ₃,—CHX^(5.1) ₂, —CH₂X^(5.1), —CN, —SO_(n5)R^(5A), —SO_(v5)NR^(5B)R^(5C),—NHNR^(5B)R^(5C), —ONR^(5B)R^(5C), —NHC(O)NHNR^(5B)R^(5C),—NHC(O)NR^(5B)R^(5C), —N(O)_(m5), —NR^(5B)R^(5C), —C(O)R^(5D),—C(O)OR^(5D), —C(O)NR^(5B)R^(5C), —OR^(5A), —NR^(5B)SO₂R^(5A),—NR^(5B)C(O)R^(5D), —NR^(5B)C(O)OR^(5D), —NR^(5B)OR^(5D), —OCX^(5.1) ₃,—OCHX^(5.1) ₂, substituted or unsubstituted alkyl, substituted orunsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl,substituted or unsubstituted heterocycloalkyl, substituted orunsubstituted aryl, or substituted or unsubstituted heteroaryl. R^(1A),R^(1B), R^(1C), R^(1D), R^(2A), R^(2B), R^(2C), R^(2D), R^(3A), R^(3B),R^(3C), R^(3D), R^(4A), R^(4B), R^(4C), R^(4D), R^(5A), R^(5B), R^(5C)and R^(5D) are independently hydrogen, halogen, —CF₃, —CCl₃, —CBr₃,—CI₃, —OH, —NH₂, —COOH, —CONH₂, —NO₂, —SH, —SO₃H, —SO₄H, —SO₂NH₂,—NHNH₂, —ONH₂, —NHC(O)NHNH₂, —NHC(O)NH₂, —NHSO₂H, —NHC(O)H, —NHC(O)—OH,—NHOH, —OCF₃, —OCCl₃, —OCBr₃, —OCI₃, —OCHF₂, —OCHCl₂, —OCHBr₂, —OCHI₂,substituted or unsubstituted alkyl, substituted or unsubstitutedheteroalkyl, substituted or unsubstituted cycloalkyl, substituted orunsubstituted heterocycloalkyl, substituted or unsubstituted aryl, orsubstituted or unsubstituted heteroaryl; R^(1B), R^(1C), R^(2B), R^(2C),R^(3B), R^(3C), R^(4B), R, R and R substituents bonded to the samenitrogen atom may optionally be joined to form a substituted orunsubstituted heterocycloalkyl or substituted or unsubstitutedheteroaryl. X^(1.1), X^(2.1), X^(3.1), X^(4.1) and X^(5.1) areindependently —Cl, —Br, —I or —F. The symbol n1, n2, n3, n4 and n5 areindependently an integer from 0 to 4. The symbols m1, m2, m3, m4, m5,v1, v2, v3, v4 and v5 are independently 1 or 2.

In embodiments, n1 is 0. In embodiments, n1 is 1. In embodiments, n1 is2. In embodiments, n1 is 3. In embodiments, n1 is 4. In embodiments, n2is 0. In embodiments, n2 is 1. In embodiments, n2 is 2. In embodiments,n2 is 3. In embodiments, n2 is 4. In embodiments, n3 is 0. Inembodiments, n3 is 1. In embodiments, n3 is 2. In embodiments, n3 is 3.In embodiments, n3 is 4. In embodiments, n4 is 0. In embodiments, n4is 1. In embodiments, n4 is 2. In embodiments, n4 is 3. In embodiments,n4 is 4. In embodiments, n5 is 0. In embodiments, n5 is 1. Inembodiments, n5 is 2. In embodiments, n5 is 3. In embodiments, n5 is 4.In embodiments, m1 is 1. In embodiments, m1 is 2. In embodiments, m2is 1. In embodiments, m2 is 2. In embodiments, m3 is 1. In embodiments,m3 is 2. In embodiments, m4 is 1. In embodiments, m4 is 2. Inembodiments, m5 is 1. In embodiments, m5 is 2. In embodiments, v1 is 1.In embodiments, v1 is 2. In embodiments, v2 is 1. In embodiments, v2 is2. In embodiments, v3 is 1. In embodiments, v3 is 2. In embodiments, v4is 1. In embodiments, v4 is 2. In embodiments, v5 is 1. In embodiments,v5 is 2.

In embodiments, Ar is substituted or unsubstituted (e.g. 5 to 6membered) heteroaryl. In embodiments, Ar is substituted or unsubstituted5 to 6 membered heteroaryl. In embodiments, Ar is unsubstitutedheteroaryl. In embodiments, Ar is unsubstituted 5 to 6 memberedheteroaryl. In embodiments, Ar is unsubstituted thienyl. In embodiments,Ar is unsubstituted 2-thienyl. In embodiments, Ar is unsubstituted2-thiophenyl. In embodiments, Ar is unsubstituted phenyl. Inembodiments, Ar is substituted phenyl.

In embodiments, the compound has Formula I A:

L¹, L², n1, n2, n3, n4, n5, m1, m2, m3, m4, m5, v1, v2, v3, v4, v5, R¹,R², R³, R⁴, and R⁵ are as described herein.

In embodiments, L¹ and L² are independently substituted or unsubstituted(e.g. C₁-C₁₀; C₁-C₅, or C₁-C₃) alkylene. In embodiments, L¹ and L² areindependently substituted or unsubstituted C₁-C₃ alkylene. Inembodiments, L¹ and L² are independently unsubstituted C₁-C₃ alkylene.In embodiments, L¹ and L² are independently —CH₂— or —CH₂CH₂—. Inembodiments, L¹ and L² are —CH₂—. In embodiments, R³ is hydrogen,—CX^(3.1) ₃, —CHX^(3.1) ₂, —CH₂X^(3.1), —CN, —SO_(n3)R^(3A),—SO_(v3)NR^(3B)R^(3C), —NHNR^(3B)R^(3C), —ONR^(3B)R^(3C),—NHC(O)NHNR^(3B)R^(3C), —NHC(O)NR^(3B)R^(3C), —N(O)_(m3),—NR^(3B)R^(3C), —C(O)R^(3D), —C(O)OR^(3D), —C(O)NR^(3B)R^(3C), —OR^(3A),—NR^(3B)SO₂R^(3A), —NR^(3B)C(O)R^(3D), —NR^(3B)C(O)OR^(3D),—NR^(3B)OR^(3D), —OCX^(3.1) ₃, —OCHX^(3.1) ₂, substituted orunsubstituted alkyl, substituted or unsubstituted heteroalkyl,substituted or unsubstituted cycloalkyl, substituted or unsubstitutedheterocycloalkyl, substituted or unsubstituted aryl, or substituted orunsubstituted heteroaryl.

In embodiments, R¹, R², R³, R⁴ and R⁵ are independently hydrogen,halogen, or substituted or unsubstituted heteroalkyl. In embodiments,R¹, R², R³, R⁴ and R⁵ are independently hydrogen, halogen orunsubstituted heteroalkyl. In embodiments, R¹, R², R³, R⁴ and R⁵ areindependently hydrogen, halogen or unsubstituted 2 to 6 memberedheteroalkyl. In embodiments, R¹, R², R³, R⁴ and R⁵ are independentlyunsubstituted 2 to 6 membered heteroalkyl. In embodiments, R¹, R², R³,R⁴ and R⁵ are hydrogen. In embodiments, R¹, R², R³, R⁴ and R⁵ areindependently hydrogen, —OCH₃ or —OCH₂CH₃. In embodiments, R¹, R², R³,R⁶, R⁷, R⁹ and R¹⁰ are independently hydrogen, halogen, —OCH₃ or—OCH₂CH₃. In embodiments, R¹, R², R³, R⁴, R⁵, R⁶, R⁷, R⁸, R⁹ and R¹⁰ areindependently hydrogen, halogen, —OCH₃ or —OCH₂CH₃. In embodiments, R⁴,R⁵ and R⁸ are hydrogen. In embodiments, R² and R³ are independently—OCH₃. In embodiments, R², R³ and R⁶ are independently —OCH₃ or—OCH₂CH₃.

In embodiments, R⁶, R⁷ and R⁹ are independently chlorine or fluorine. Inembodiments, R⁶ is —OCH₂CH₃. In embodiments, R¹, R⁴ and R⁵ are hydrogen.In embodiments, R² and R³ are independently —OCH₃. In embodiments, R⁶ ishalogen. In embodiments, R⁷ is halogen. In embodiments, R⁹ is halogen.In embodiments, R⁶ is unsubstituted C₁-C₃ alkoxy. In embodiments, R⁷ isunsubstituted C₁-C₃ alkoxy. In embodiments, R² is unsubstituted C₁-C₃alkoxy. In embodiments, R³ is unsubstituted C₁-C₃ alkoxy. Inembodiments, R⁴ is unsubstituted C₁-C₃ alkoxy.

In embodiments, R¹, R², R⁴ and R⁵ are independently hydrogen, halogen,or substituted or unsubstituted heteroalkyl and R³ is hydrogen orsubstituted or unsubstituted heteroalkyl. In embodiments, R¹, R², R⁴ andR⁵ are independently hydrogen, halogen or unsubstituted heteroalkyl andR³ is hydrogen or unsubstituted heteroalkyl. In embodiments, R¹, R², R⁴and R⁵ are independently hydrogen, halogen or unsubstituted 2 to 6membered heteroalkyl and R³ is hydrogen or unsubstituted 2 to 6 memberedheteroalkyl. In embodiments, R¹, R², R³, R⁴ and R⁵ are independentlyunsubstituted 2 to 6 membered heteroalkyl. In embodiments, R¹, R², R³,R⁴ and R⁵ are hydrogen. In embodiments, R¹, R⁴ and R⁵ are hydrogen andR² and R³ are independently unsubstituted 2 to 6 membered heteroalkyl.In embodiments, R¹, R², R³, R⁴ and R⁵ are independently hydrogen, —OCH₃or —OCH₂CH₃. In embodiments, R¹, R⁴ and R⁵ are hydrogen and R² and R³are independently —OCH₃ or —OCH₂CH₃. In embodiments, R¹, R⁴ and R⁵ arehydrogen, and R² and R³ are —OCH₃.

R¹, R², R⁴, R⁵, R⁶, R⁷, R⁸, R⁹ and R¹⁰ are independently hydrogen,halogen, or substituted or unsubstituted (e.g. 2 to 6 membered)heteroalkyl and R³ is hydrogen, substituted or unsubstitutedheteroalkyl. In embodiments, R¹, R², R⁶, R⁷, R⁹ and R¹⁰ areindependently hydrogen, halogen, —OCH₃ or —OCH₂CH₃, and R³ is hydrogen,—OCH₃ or —OCH₂CH₃. In embodiments, R¹, R², R⁴, R⁵, R⁶, R⁷, R⁸, R⁹ andR¹⁰ are independently hydrogen, halogen, —OCH₃ or —OCH₂CH₃. Inembodiments, R⁴, R⁵ and R⁸ are hydrogen. In embodiments, R⁴, R⁵, R⁸ andR¹⁰ are hydrogen. In embodiments, R⁴, R⁵, R⁸, R⁹ and R¹⁰ are hydrogen.In embodiments, R⁴, R⁵, R⁷, R⁸, R⁹ and R¹⁰ are hydrogen. In embodiments,R² and R³ are independently —OCH₃ or —OCH₂CH₃. In embodiments, R², R³and R⁶ are independently —OCH₃ or —OCH₂CH₃. In embodiments, R⁶, R⁷ andR⁹ are independently chlorine or fluorine. In embodiments, R⁶ is—OCH₂CH₃. In embodiments, R¹, R⁴ and R⁵ are hydrogen. In embodiments, R²and R³ are independently —OCH₃. In embodiments, R⁶ is halogen. Inembodiments, R⁷ is halogen. In embodiments, R⁹ is halogen. Inembodiments, R⁶ is unsubstituted C₁-C₃ alkoxy. In embodiments, R⁷ isunsubstituted C₁-C₃ alkoxy. In embodiments, R² is unsubstituted C₁-C₃alkoxy. In embodiments, R³ is unsubstituted C₁-C₃ alkoxy. Inembodiments, R⁴ is unsubstituted C₁-C₃ alkoxy.

In embodiments, when L¹ and L² are independently unsubstituted C₁-C₃alkylene, R² and R³ are —OCH₃, and R⁷, R⁸, R⁹ and R¹⁰ are hydrogen, thenR⁶ is not —OCH₃. In embodiments, when L¹ and L² are —CH₂₋, R² and R³ areunsubstituted 2 to 6 heteroalkyl, and R⁷, R⁸, R⁹ and R¹⁰ are hydrogen,then R⁶ is not —OCH₃. In embodiments, when L¹ and L² are —CH₂₋, R² andR³ are independently —OCH₃ or —OCH₂CH₃, and R⁷, R⁸, R⁹ and R¹⁰ arehydrogen, then R⁶ is not —OCH₃. In embodiments, when L¹ and L² are—CH₂—, R² and R³ are independently —OCH₃ or —OCH₂CH₃, R⁸, R⁹ and R¹⁰ arehydrogen, then R⁶ is not —OCH₃. In embodiments, when L¹ and L² areindependently unsubstituted C₁-C₃ alkylene, R² and R³ are —OCH₃, R⁶, R⁸,R⁹ and R¹⁰ are hydrogen, then R⁷ is not —OCH₃. In embodiments, when L¹and L² are —CH₂—, R² and R³ are unsubstituted 2 to 6 heteroalkyl, R⁶,R⁸, R⁹ and R¹⁰ are hydrogen, then R⁷ is not —OCH₃. In embodiments, whenL¹ and L² are —CH₂—, R² and R³ are independently —OCH₃ or —OCH₂CH₃, R⁶,R⁸, R⁹ and R¹⁰ are hydrogen, then R⁷ is not —OCH₃. In embodiments, R⁶ is—OCH₂CH₃ and R⁷ is hydrogen. In embodiments, R⁷ is —OCH₂CH₃ and R⁶ ishydrogen. In embodiments, R⁷ is —OCH₂CH₃. In embodiments, R⁶ is—OCH₂CH₃. In embodiments, when R⁷ is-OCH₃, R⁶ is not hydrogen. Inembodiments, when R⁶ is-OCH₃, R⁷ is not hydrogen.

R⁶ is hydrogen, halogen, —CX^(6.1) ₃, —CHX^(6.1) ₂, —CH₂X^(6.1), —CN,—SO_(n6)R^(6A), —SO_(v6)NR^(6B)R^(6C), —NHNR^(6B)R^(6C),—ONR^(6B)R^(6C), —NHC(O)NHNR^(6B)R^(6C), —NHC(O)NR^(6B)R^(6C),—N(O)_(m6), —NR^(6B)R^(6C), —C(O)R^(6D), —C(O)OR^(6D),—C(O)NR^(6B)R^(6C), —OR^(6A), —NR^(6B)SO₂R^(6A), —NR^(6B)C(O)R^(6D),—NR^(6B)C(O)OR^(6D), —NR^(6B)OR^(6D), —OCX^(6.1) ₃, —OCHX^(6.1) ₂,substituted or unsubstituted alkyl, substituted or unsubstitutedheteroalkyl, substituted or unsubstituted cycloalkyl, substituted orunsubstituted heterocycloalkyl, substituted or unsubstituted aryl, orsubstituted or unsubstituted heteroaryl.

R⁷ is hydrogen, halogen, —CX^(7.1), —CHX^(7.1) ₂, —CH₂X^(7.1), —CN,—SO_(n7)R^(7A), —SO_(v7)NR^(7B)R^(7C), —NHNR^(7B)R^(7C),—ONR^(7B)R^(7C), —NHC(O)NHNR^(7B)R^(7C), —NHC(O)NR^(7B)R^(7C),—N(O)_(m7), —NR^(7B)R^(7C), —C(O)R^(7D), —C(O)OR^(7D),—C(O)NR^(7B)R^(7C), —OR^(7A), —NR^(7B)SO₂R^(7A), —NR^(7A)C(O)R^(7C),—NR^(7B)C(O)OR^(7D), —NR^(7B)OR^(7D), —OCX^(7.1) ₃, —OCHX^(7.1) ₂,substituted or unsubstituted alkyl, substituted or unsubstitutedheteroalkyl, substituted or unsubstituted cycloalkyl, substituted orunsubstituted heterocycloalkyl, substituted or unsubstituted aryl, orsubstituted or unsubstituted heteroaryl.

R⁸ is hydrogen, halogen, —CX^(8.1) ₃, —CHX^(8.1) ₂, —CH₂X^(8.1), —CN,—SO_(n8)R^(8A), —SO_(v8)NR^(8B)R^(8C), —NHNR^(8B)R^(8C),—ONR^(8B)R^(8C), —NHC(O)NHNR^(8B)R^(8C), —NHC(O)NR^(8B)R^(8C),—N(O)_(m8), —NR^(8B)R^(8C), —C(O)R^(8D), —C(O)OR^(8D),—C(O)NR^(8B)R^(8C), —OR^(8A), —NR^(8B)SO₂R^(8A), —NR^(8B)C(O)R^(8D),—NR^(8B)C(O)OR^(8D), —NR^(8B)OR^(8D), —OCX^(8.1) ₃, —OCHX^(8.1) ₂,substituted or unsubstituted alkyl, substituted or unsubstitutedheteroalkyl, substituted or unsubstituted cycloalkyl, substituted orunsubstituted heterocycloalkyl, substituted or unsubstituted aryl, orsubstituted or unsubstituted heteroaryl.

R⁹ is hydrogen, halogen, —CX^(9.1) ₃, —CHX^(9.1) ₂, —CH₂X^(9.1), —CN,—SO_(n9)R^(9A), —SO_(v9)NR^(9B)R^(9C), —NHNR^(9B)R^(9C),—ONR^(9B)R^(9C), —NHC(O)NHNR^(9B)R^(9C), —NHC(O)NR^(9B)R^(9C),—N(O)_(m9), —NR^(9B)R^(9C), —C(O)R^(9D), —C(O)OR^(9D),—C(O)NR^(9B)R^(9C), —OR^(9A), —NR^(9B)SO₂R^(9A), —NR^(9B)C(O)R^(9D),—NR^(9B)C(O)OR^(9D), —NR^(9B)OR^(9D), —OCX^(9.1) ₃, —OCHX^(9.1) ₂,substituted or unsubstituted alkyl, substituted or unsubstitutedheteroalkyl, substituted or unsubstituted cycloalkyl, substituted orunsubstituted heterocycloalkyl, substituted or unsubstituted aryl, orsubstituted or unsubstituted heteroaryl.

R¹⁰ is hydrogen, halogen, —CX^(10.1) ₃, —CHX^(10.1) ₂, —CH₂X^(10.1),—CN, —SO_(n10)R^(10A), —SO_(v10)NR^(10B)R^(10C), —NHNR^(10B)R^(10C),—ONR^(10B)R^(10C), —NHC(O)NHNR^(10B)R^(10C), —NHC(O)NR^(10B)R^(10C),—N(O)_(m10), —NR^(10B)R^(10C), —C(O)R^(10D), —C(O)OR^(10D),—C(O)NR^(10B)R^(10C), —OR^(10A), —NR^(10B)SO₂R^(10A),—NR^(10B)C(O)R^(10D), —NR^(10B)C(O)OR^(10D), —NR^(10B)OR^(10D),—OCX^(10.1) ₃, —OCHX^(10.1) ₂, substituted or unsubstituted alkyl,substituted or unsubstituted heteroalkyl, substituted or unsubstitutedcycloalkyl, substituted or unsubstituted heterocycloalkyl, substitutedor unsubstituted aryl, or substituted or unsubstituted heteroaryl. Thesymbol n6, n7, n8, n9 and n10 are independently an integer from 0 to 4.The symbols m6, m7, m8, m9, m10, v6, v7, v8, v9 and v10 areindependently 1 or 2.

In embodiments, n6 is 0. In embodiments, n6 is 1. In embodiments, n6 is2. In embodiments, n6 is 3. In embodiments, n6 is 4. In embodiments, n7is 0. In embodiments, n7 is 1. In embodiments, n7 is 2. In embodiments,n7 is 3. In embodiments, n7 is 4. In embodiments, n8 is 0. Inembodiments, n8 is 1. In embodiments, n8 is 2. In embodiments, n8 is 3.In embodiments, n8 is 4. In embodiments, n9 is 0. In embodiments, n9is 1. In embodiments, n9 is 2. In embodiments, n9 is 3. In embodiments,n9 is 4. In embodiments, n10 is 0. In embodiments, n10 is 1. Inembodiments, n10 is 2. In embodiments, n10 is 3. In embodiments, n10 is4. In embodiments, m6 is 1. In embodiments, m6 is 2. In embodiments, m7is 1. In embodiments, m7 is 2. In embodiments, m8 is 1. In embodiments,m8 is 2. In embodiments, m9 is 1. In embodiments, m9 is 2. Inembodiments, m10 is 1. In embodiments, m10 is 2. In embodiments, v6is 1. In embodiments, v6 is 2. In embodiments, v7 is 1. In embodiments,v7 is 2. In embodiments, v8 is 1. In embodiments, v8 is 2. Inembodiments, v9 is 1. In embodiments, v9 is 2. In embodiments, v10 is 1.In embodiments, v10 is 2.

R^(1A), R^(1B), R^(1C), R^(1D), R^(2A), R^(2B), R^(2C), R^(2D), R^(3A),R^(3B), R^(3C), R^(3D), R^(4A), R^(4B), R^(4C), R^(4D), R^(5A), R^(5B),R^(5C), R^(5D), R^(6A), R^(6B), R^(6C), R^(6D), R^(7A), R^(7B), R^(7C),R^(7D), R^(8A), R^(8B), R^(8C), R^(8D), R^(9A), R^(9B), R^(9C), R^(9D),R^(10A), R^(10B), R^(10C) and R^(10D) are independently hydrogen,halogen, —CF₃, —CCl₃, —CBr₃, —CI₃, —OH, —NH₂, —COOH, —CONH₂, —NO₂, —SH,—SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂, —ONH₂, —NHC(O)NHNH₂, —NHC(O)NH₂, —NHSO₂H,—NHC(O)H, —NHC(O)—OH, —NHOH, —OCF₃, —OCCl₃, —OCBr₃, —OCI₃, —OCHF₂,—OCHCl₂, —OCHBr₂, —OCHI₂, substituted or unsubstituted alkyl,substituted or unsubstituted heteroalkyl, substituted or unsubstitutedcycloalkyl, substituted or unsubstituted heterocycloalkyl, substitutedor unsubstituted aryl, or substituted or unsubstituted heteroaryl.

In embodiments, R^(1B), R^(1C), R^(2B), R^(2C), R^(3B), R^(3C), R^(4B),R^(4C), R^(5B), R^(5C), R^(6B), R^(6C), R^(7B), R^(7C), R^(8B), R^(8C),R^(9B), R^(9C), R^(10B) and R^(10C) substituents bonded to the samenitrogen atom may optionally be joined to form a substituted orunsubstituted heterocycloalkyl or substituted or unsubstitutedheteroaryl.

X^(1.1), X^(2.1), X^(3.1), X^(4.1), X^(5.1), X^(6.1), X^(7.1), X^(8.1),X^(9.1) and X^(10.1) are independently —Cl, —Br, —I or —F.

In embodiments, R¹ is independently hydrogen, halogen, —CX^(1.1) ₃,—CHX^(1.1) ₂, —CH₂X^(1.1), —CN, —SO_(n1)R^(1A), —SO_(v1)NR^(1B)R^(1C),—NHNR^(1B)R^(1C), —ONR^(1B)R^(1C), —NHC(O)NHNR^(1B)R^(1C),—NHC(O)NR^(1B)R^(1C), —N(O)_(m1), —NR^(1B)R^(1C), —C(O)R^(1D),—C(O)OR^(1D), —C(O)NR^(1B)R^(1C), —OR^(1A), —NR^(1B)SO₂R^(1A),—NR^(1B)C(O)R^(1D), —NR^(1B)C(O)OR^(1D), —NR^(1B)OR^(1D), —OCX^(1.1) ₃,—OCHX^(1.1) ₂ (e.g. hydrogen, halogen, —CF₃, —CCl₃, —CBr₃, —CI₃, —CN,—OH, —NH₂, —COOH, —CONH₂, —NO₂, —SH, —SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂,—ONH₂, —NHC(O)NHNH₂, —NHC(O)NH₂, —NHSO₂H, —NHC(O)H, —NHC(O)OH, —NHOH,—OCF₃, —OCCl₃, —OCBr₃, —OCI₃, —OCHF₂, —OCHCl₂, —OCHBr₂, —OCHI₂),R^(1E)-substituted or unsubstituted alkyl, R^(1E)-substituted orunsubstituted heteroalkyl, R^(1E)-substituted or unsubstitutedcycloalkyl, R^(1E)-substituted or unsubstituted heterocycloalkyl,R^(1E)-substituted or unsubstituted aryl, or R^(1E)-substituted orunsubstituted heteroaryl. In embodiments, R¹ is independently hydrogen,halogen, —CX^(1.1) ₃, —CHX^(1.1) ₂, —CH₂X^(1.1), —CN, —SO_(n1)R^(1A),—SO_(v1)NR^(1B)R^(1C), —NHNR^(1B)R^(1C), —ONR^(1B)R^(1C),—NHC(O)NHNR^(1B)R^(1C), —NHC(O)NR^(1B)R^(1C), —N(O)_(m1),—NR^(1B)R^(1C), —C(O)R^(1D), —C(O)OR^(1D), —C(O)NR^(1B)R^(1C), —OR^(1A),—NR^(1B)SO₂R^(1A), —NR^(1B)C(O)R^(1D), —NR^(1B)C(O)OR^(1D),—NR^(1B)OR^(1D), —OCX^(1.1) ₃, —OCHX^(1.1) ₂ (e.g. hydrogen, halogen,—CF₃, —CCl₃, —CBr₃, —CI₃, —CN, —OH, —NH₂, —COOH, —CONH₂, —NO₂, —SH,—SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂, —ONH₂, —NHC(O)NHNH₂, —NHC(O)NH₂, —NHSO₂H,—NHC(O)H, —NHC(O)OH, —NHOH, —OCF₃, —OCCl₃, —OCBr₃, —OCI₃, —OCHF₂,—OCHCl₂, —OCHBr₂, —OCHI₂), R^(1E)-substituted or unsubstituted C₁-C₆alkyl, R^(1E)-substituted or unsubstituted 2 to 6 membered heteroalkyl,R^(1E)-substituted or unsubstituted C₃-C₆ cycloalkyl, R^(1E)-substitutedor unsubstituted 3 to 6 membered heterocycloalkyl, R^(1E)-substituted orunsubstituted phenyl, or R^(1E)-substituted or unsubstituted 5 to 6membered heteroaryl. In embodiments, R¹ is unsubstituted 2 to 6 memberedheteroalkyl. In embodiments, R¹ is unsubstituted C₁-C₃ alkoxy. Inembodiments, R¹ is —OCH₃ or —OCH₂CH₃. In embodiments, R¹ is —OCH₃. Inembodiments, R¹ is hydrogen or unsubstituted or substituted C₁-C₃ alkyl.In embodiments, R¹ is hydrogen or unsubstituted C₁-C₃ alkyl. Inembodiments, R¹ is hydrogen, methyl or ethyl. In embodiments, R¹ ishydrogen. R^(1E) is independently oxo, halogen, —CF₃, —CCl₃, —CBr₃,—CI₃, —CN, —OH, —NH₂, —COOH, —CONH₂, —NO₂, —SH, —SO₃H, —SO₄H, —SO₂NH₂,—NHNH₂, —ONH₂, —NHC(O)NHNH₂, —NHC(O)NH₂, —NHSO₂H, —NHC(O)H, —NHC(O)OH,—NHOH, —OCF₃, —OCCl₃, —OCBr₃, —OCI₃, —OCHF₂, —OCHCl₂, —OCHBr₂, —OCHI₂,R^(1F)-substituted or unsubstituted alkyl, R^(1F)-substituted orunsubstituted heteroalkyl, R^(1F)-substituted or unsubstitutedcycloalkyl, R^(1F)-substituted or unsubstituted heterocycloalkyl,R^(1F)-substituted or unsubstituted aryl, or R^(1F)-substituted orunsubstituted heteroaryl. In embodiments, R^(1E) is independently oxo,halogen, —CF₃, —CCl₃, —CBr₃, —CI₃, —CN, —OH, —NH₂, —COOH, —CONH₂, —NO₂,—SH, —SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂, —ONH₂, —NHC(O)NHNH₂, —NHC(O)NH₂,—NHSO₂H, —NHC(O)H, —NHC(O)OH, —NHOH, —OCF₃, —OCCl₃, —OCBr₃, —OCI₃,—OCHF₂, —OCHCl₂, —OCHBr₂, —OCHI₂, R^(1F)-substituted or unsubstitutedC₁-C₆ alkyl, R^(1F)-substituted or unsubstituted 2 to 6 memberedheteroalkyl, R^(1F)-substituted or unsubstituted C₃-C₆ cycloalkyl,R^(1F)-substituted or unsubstituted 3 to 6 membered heterocycloalkyl,R^(1F)-substituted or unsubstituted phenyl, or R^(1F)-substituted orunsubstituted 5 to 6 membered heteroaryl.

In embodiments, R² is independently hydrogen, halogen, —CX^(2.1) ₃,—CHX^(2.1) ₂, —CH₂X^(2′), —CN, —SO_(n2)R^(2A), —SO_(v2)NR^(2B)R^(2C),—NHNR^(2B)R^(2C), —ONR^(2B)R^(2C), —NHC(O)NHNR^(2B)R^(2C),—NHC(O)NR^(2B)R^(2C), —N(O)_(m2), —NR^(2B)R^(2C), —C(O)R^(2D),—C(O)OR^(2D), —C(O)NR^(2B)R^(2C), —OR^(2A), —NR^(2B)SO₂R^(2A),—NR^(2B)C(O)R^(2D), —NR^(2B)C(O)OR^(2D), —NR^(2B)OR^(2D), —OCX^(2.1) ₃,—OCHX^(2.1) ₂ (e.g. hydrogen, halogen, —CF₃, —CCl₃, —CBr₃, —CI₃, —CN,—OH, —NH₂, —COOH, —CONH₂, —NO₂, —SH, —SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂,—ONH₂, —NHC(O)NHNH₂, —NHC(O)NH₂, —NHSO₂H, —NHC(O)H, —NHC(O)OH, —NHOH,—OCF₃, —OCCl₃, —OCBr₃, —OCI₃, —OCHF₂, —OCHCl₂, —OCHBr₂), —OCHI₂,R^(2E)-substituted or unsubstituted alkyl, R^(2E)-substituted orunsubstituted heteroalkyl, R^(2E)-substituted or unsubstitutedcycloalkyl, R^(2E)-substituted or unsubstituted heterocycloalkyl,R^(2E)-substituted or unsubstituted aryl, or R^(2E)-substituted orunsubstituted heteroaryl. In embodiments, R² is independently hydrogen,halogen, —CX^(2.1) ₃, —CHX^(2.1) ₂, —CH₂X^(2.1), —CN, —SO_(n2)R^(2A),—SO_(v2)NR^(2B)R^(2C), —NHNR^(2B)R^(2C), —ONR^(2B)R^(2C),—NHC(O)NHNR^(2B)R^(2C), —NHC(O)NR^(2B)R^(2C), —N(O)_(m2),—NR^(2B)R^(2C), —C(O)R^(2D), —C(O)OR^(2D), —C(O)NR^(2B)R^(2C), —OR^(2A),—NR^(2B)SO₂R^(2A), —NR^(2B)C(O)R^(2D), —NR^(2B)C(O)OR^(2D),—NR^(2B)OR^(2D), —OCX² s, —OCHX^(2.1) ₂ (e.g. hydrogen, halogen, —CF₃,—CCl₃, —CBr₃, —CI₃, —CN, —OH, —NH₂, —COOH, —CONH₂, —NO₂, —SH, —SO₃H,—SO₄H, —SO₂NH₂, —NHNH₂, —ONH₂, —NHC(O)NHNH₂, —NHC(O)NH₂, —NHSO₂H,—NHC(O)H, —NHC(O)OH, —NHOH, —OCF₃, —OCCl₃, —OCBr₃, —OCI₃, —OCHF₂,—OCHCl₂, —OCHBr₂, —OCHI₂), R^(2E)-substituted or unsubstituted C₁-C₆alkyl, R^(2E)-substituted or unsubstituted 2 to 6 membered heteroalkyl,R^(2E)-substituted or unsubstituted C₃-C₆ cycloalkyl, R^(2E)-substitutedor unsubstituted 3 to 6 membered heterocycloalkyl, R^(2E)-substituted orunsubstituted phenyl, or R^(2E)-substituted or unsubstituted 5 to 6membered heteroaryl. In embodiments, R² is unsubstituted alkoxy. Inembodiments, R² is unsubstituted C₁-C₃ alkoxy. In embodiments, R² is—OCH₃ or —OCH₂CH₃. In embodiments, R² is —OCH₃.

R^(2E) is independently oxo, halogen, —CF₃, —CCl₃, —CBr₃, —CI₃, —CN,—OH, —NH₂, —COOH, —CONH₂, —NO₂, —SH, —SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂,—ONH₂, —NHC(O)NHNH₂, —NHC(O)NH₂, —NHSO₂H, —NHC(O)H, —NHC(O)OH, —NHOH,—OCF₃, —OCCl₃, —OCBr₃, —OCI₃, —OCHF₂, —OCHCl₂, —OCHBr₂, —OCHI₂,R^(2F)-substituted or unsubstituted alkyl, R^(2F)-substituted orunsubstituted heteroalkyl, R^(2F)-substituted or unsubstitutedcycloalkyl, R^(2F)-substituted or unsubstituted heterocycloalkyl,R^(2F)-substituted or unsubstituted aryl, or R^(2F)-substituted orunsubstituted heteroaryl. In embodiments, R^(2E) is independently oxo,halogen, —CF₃, —CCl₃, —CBr₃, —CI₃, —CN, —OH, —NH₂, —COOH, —CONH₂, —NO₂,—SH, —SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂, —ONH₂, —NHC(O)NHNH₂, —NHC(O)NH₂,—NHSO₂H, —NHC(O)H, —NHC(O)OH, —NHOH, —OCF₃, —OCCl₃, —OCBr₃, —OCI₃,—OCHF₂, —OCHCl₂, —OCHBr₂, —OCHI₂, R^(2F)-substituted or unsubstitutedC₁-C₆ alkyl, R^(2F)-substituted or unsubstituted 2 to 6 memberedheteroalkyl, R^(2F)-substituted or unsubstituted C₃-C₆ cycloalkyl,R^(2F)-substituted or unsubstituted 3 to 6 membered heterocycloalkyl,R^(2F)-substituted or unsubstituted phenyl, or R^(2F)-substituted orunsubstituted 5 to 6 membered heteroaryl.

In embodiments, R³ is independently hydrogen, halogen, —CX^(3.1) ₃,—CHX^(3.1) ₂, —CH₂X^(3.1), —CN, —SO_(n3)R^(3A), —SO_(v3)NR^(3B)R^(3C),—NHNR^(3B)R^(3C), —ONR^(3B)R^(3C), —NHC(O)NHNR^(3B)R^(3C),—NHC(O)NR^(3B)R^(3C), —N(O)_(m3), —NR^(3B)R^(3C), —C(O)R^(3D),—C(O)OR^(3D), —C(O)NR^(3B)R^(3C), —OR^(3A), —NR^(3B)SO₂R^(3A),—NR^(3B)C(O)R^(3D), —NR^(3B)C(O)OR^(3D), —NR^(3B)OR^(3D), —OCX^(3.1) ₃,—OCHX^(3.1) ₂ (e.g. hydrogen, halogen, —CF₃, —CCl₃, —CBr₃, —CI₃, —CN,—OH, —NH₂, —COOH, —CONH₂, —NO₂, —SH, —SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂,—ONH₂, —NHC(O)NHNH₂, —NHC(O)NH₂, —NHSO₂H, —NHC(O)H, —NHC(O)OH, —NHOH,—OCF₃, —OCCl₃, —OCBr₃, —OCI₃, —OCHF₂, —OCHCl₂, —OCHBr₂, —OCHI₂),R^(3E)-substituted or unsubstituted alkyl, R^(3E)-substituted orunsubstituted heteroalkyl, R^(3E)-substituted or unsubstitutedcycloalkyl, R^(3E)-substituted or unsubstituted heterocycloalkyl,R^(3E)-substituted or unsubstituted aryl, or R^(3E)-substituted orunsubstituted heteroaryl. In embodiments, R³ is independently hydrogen,halogen, —CX^(3.1) ₃, —CHX^(3.1) ₂, —CH₂X^(3.1), —CN, —SO_(n3)R^(3A),—SO_(v3)NR^(3B)R^(3C), —NHNR^(3B)R^(3C), —ONR^(3B)R^(3C),—NHC(O)NHNR^(3B)R^(3C), —NHC(O)NR^(3B)R^(3C), —N(O)_(m3),—NR^(3B)R^(3C), —C(O)R^(3D), —C(O)OR^(3D), —C(O)NR^(3B)R^(3C), —OR^(3A),—NR^(3B)SO₂R^(3A), —NR^(3B)C(O)R^(3D), —NR^(3B)C(O)OR^(3D),—NR^(3B)OR^(3D), —OCX^(3.1) ₃, —OCHX^(3.1) ₂ (e.g. hydrogen, halogen,—CF₃, —CCl₃, —CBr₃, —CI₃, —CN, —OH, —NH₂, —COOH, —CONH₂, —NO₂, —SH,—SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂, —ONH₂, —NHC(O)NHNH₂, —NHC(O)NH₂, —NHSO₂H,—NHC(O)H, —NHC(O)OH, —NHOH, —OCF₃, —OCCl₃, —OCBr₃, —OCI₃, —OCHF₂,—OCHCl₂, —OCHBr₂, —OCHI₂), R^(3E)-substituted or unsubstituted C₁-C₆alkyl, R^(3E)-substituted or unsubstituted 2 to 6 membered heteroalkyl,R^(3E)-substituted or unsubstituted C₃-C₆ cycloalkyl, R^(3E)-substitutedor unsubstituted 3 to 6 membered heterocycloalkyl, R^(3E)-substituted orunsubstituted phenyl, or R^(3E)-substituted or unsubstituted 5 to 6membered heteroaryl. In embodiments, R³ is unsubstituted 2 to 6 memberedheteroalkyl. In embodiments, R³ is unsubstituted alkoxy. In embodiments,R³ is unsubstituted C₁-C₃ alkoxy. In embodiments, R³ is —OCH₃ or—OCH₂CH₃. In embodiments, R³ is —OCH₃.

In embodiments, R³ is independently hydrogen, —CX^(3.1) ₃, —CHX^(3.1) ₂,—CH₂X^(3.1), —CN, —SO_(n3)R^(3A), —SO_(v3)NR^(3B)R^(3C),—NHNR^(3B)R^(3C), —ONR^(3B)R^(3C), —NHC(O)NHNR^(3B)R^(3C),—NHC(O)NR^(3B)R^(3C), —N(O)_(m3), —NR^(3B)R^(3C), —C(O)R^(3D),—C(O)OR^(3D), —C(O)NR^(3B)R^(3C), —OR^(3A), —NR^(3B)SO₂R^(3A),—NR^(3B)C(O)R^(3D), —NR^(3B)C(O)OR^(3D), —NR^(3B)OR^(3D), —OCX^(3.1) ₃,—OCHX^(3.1) ₂ (e.g. hydrogen, halogen, —CF₃, —CCl₃, —CBr₃, —CI₃, —CN,—OH, —NH₂, —COOH, —CONH₂, —NO₂, —SH, —SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂,—ONH₂, —NHC(O)NHNH₂, —NHC(O)NH₂, —NHSO₂H, —NHC(O)H, —NHC(O)OH, —NHOH,—OCF₃, —OCCl₃, —OCBr₃, —OCI₃, —OCHF₂, —OCHCl₂, —OCHBr₂, —OCHI₂),R^(3E)-substituted or unsubstituted alkyl, R^(3E)-substituted orunsubstituted heteroalkyl, R^(3E)-substituted or unsubstitutedcycloalkyl, R^(3E)-substituted or unsubstituted heterocycloalkyl,R^(3E)-substituted or unsubstituted aryl, or R^(3E)-substituted orunsubstituted heteroaryl. In embodiments, R³ is independently hydrogen,—CX^(3.1) ₃, —CHX^(3.1) ₂, —CH₂X^(3.1), —CN, —SO_(n3)R^(3A),—SO_(v3)NR^(3B)R^(3C), —NHNR^(3B)R^(3C), —ONR^(3B)R^(3C),—NHC(O)NHNR^(3B)R^(3C), —NHC(O)NR^(3B)R^(3C), —N(O)_(m3),—NR^(3B)R^(3C), —C(O)R^(3D), —C(O)OR^(3D), —C(O)NR^(3B)R^(3C), —OR^(3A),—NR^(3B)SO₂R^(3A), —NR^(3B)C(O)R^(3D), —NR^(3B)C(O)OR^(3D),—NR^(3B)OR^(3D), —OCX^(3.1) ₃, —OCHX^(3.1) ₂ (e.g. hydrogen, halogen,—CF₃, —CCl₃, —CBr₃, —CI₃, —CN, —OH, —NH₂, —COOH, —CONH₂, —NO₂, —SH,—SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂, —ONH₂, —NHC(O)NHNH₂, —NHC(O)NH₂, —NHSO₂H,—NHC(O)H, —NHC(O)OH, —NHOH, —OCF₃, —OCCl₃, —OCBr₃, —OCI₃, —OCHF₂,—OCHCl₂, —OCHBr₂, —OCHI₂), R^(3E)-substituted or unsubstituted C₁-C₆alkyl, R^(3E)-substituted or unsubstituted 2 to 6 membered heteroalkyl,R^(3E)-substituted or unsubstituted C₃-C₆ cycloalkyl, R^(3E)-substitutedor unsubstituted 3 to 6 membered heterocycloalkyl, R^(3E)-substituted orunsubstituted phenyl, or R^(3E)-substituted or unsubstituted 5 to 6membered heteroaryl. In embodiments, R³ is unsubstituted 2 to 6 memberedheteroalkyl. In embodiments, R³ is unsubstituted alkoxy. In embodiments,R³ is unsubstituted C₁-C₃ alkoxy. In embodiments, R³ is —OCH₃ or—OCH₂CH₃. In embodiments, R³ is —OCH₃.

R^(3E) is independently oxo, halogen, —CF₃, —CCl₃, —CBr₃, —CI₃, —CN,—OH, —NH₂, —COOH, —CONH₂, —NO₂, —SH, —SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂,—ONH₂, —NHC(O)NHNH₂, —NHC(O)NH₂, —NHSO₂H, —NHC(O)H, —NHC(O)OH, —NHOH,—OCF₃, —OCCl₃, —OCBr₃, —OCI₃, —OCHF₂, —OCHCl₂, —OCHBr₂, —OCHI₂,R^(3F)-substituted or unsubstituted alkyl, R^(3F)-substituted orunsubstituted heteroalkyl, R^(3F)-substituted or unsubstitutedcycloalkyl, R^(3F)-substituted or unsubstituted heterocycloalkyl,R^(3F)-substituted or unsubstituted aryl, or R^(3F)-substituted orunsubstituted heteroaryl. In embodiments, R^(3E) is independently oxo,halogen, —CF₃, —CCl₃, —CBr₃, —CI₃, —CN, —OH, —NH₂, —COOH, —CONH₂, —NO₂,—SH, —SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂, —ONH₂, —NHC(O)NHNH₂, —NHC(O)NH₂,—NHSO₂H, —NHC(O)H, —NHC(O)OH, —NHOH, —OCF₃, —OCCl₃, —OCBr₃, —OCI₃,—OCHF₂, —OCHCl₂, —OCHBr₂, —OCHI₂, R^(3F)-substituted or unsubstitutedC₁-C₆ alkyl, R^(3F)-substituted or unsubstituted 2 to 6 memberedheteroalkyl, R^(3F)-substituted or unsubstituted C₃-C₆ cycloalkyl,R^(3F)-substituted or unsubstituted 3 to 6 membered heterocycloalkyl,R^(3F)-substituted or unsubstituted phenyl, or R^(3F)-substituted orunsubstituted 5 to 6 membered heteroaryl.

In embodiments, R⁴ is independently hydrogen, halogen, —CX^(4.1) ₃,—CHX^(4.1) ₂, —CH₂X^(4.1), —CN, —SO_(n4)R^(4A), —SO_(v4)NR^(4B)R^(4C),—NHNR^(4B)R^(4C), —ONR^(4B)R^(4C), —NHC(O)NHNR^(4B)R^(4C),—NHC(O)NR^(4B)R^(4C), —N(O)_(m4), —NR^(4B)R^(4C), —C(O)R^(4D),—C(O)OR^(4D), —C(O)NR^(4B)R^(4C), —OR^(4A), —NR^(4B)SO₂R^(4A),—NR^(4B)C(O)R^(4D), —NR^(4B)C(O)OR^(4D), —NR^(4B)OR^(4D), —OCX^(4.1) ₃,—OCHX^(4.1) ₂ (e.g. hydrogen, halogen, —CF₃, —CCl₃, —CBr₃, —CI₃, —CN,—OH, —NH₂, —COOH, —CONH₂, —NO₂, —SH, —SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂,—ONH₂, —NHC(O)NHNH₂, —NHC(O)NH₂, —NHSO₂H, —NHC(O)H, —NHC(O)OH, —NHOH,—OCF₃, —OCCl₃, —OCBr₃, —OCI₃, —OCHF₂, —OCHCl₂, —OCHBr₂, —OCHI₂),R^(4E)-substituted or unsubstituted alkyl, R^(4E)-substituted orunsubstituted heteroalkyl, R^(4E)-substituted or unsubstitutedcycloalkyl, R^(4E)-substituted or unsubstituted heterocycloalkyl,R^(4E)-substituted or unsubstituted aryl, or R^(4E)-substituted orunsubstituted heteroaryl. In embodiments, R⁴ is independently hydrogen,halogen, —CX^(4.1) ₃, —CHX^(4.1) ₂, —CH₂X^(4.1), —CN, —SO_(n4)R^(4A),—SO_(v4)NR^(4B)R^(4C), —NHNR^(4B)R^(4C), —ONR^(4B)R^(4C),—NHC(O)NHNR^(4B)R^(4C), —NHC(O)NR^(4B)R^(4C), —N(O)_(m4),—NR^(4B)R^(4C), —C(O)R^(4D), —C(O)OR^(4D), —C(O)NR^(4B)R^(4C), —OR^(4A),—NR^(4B)SO₂R^(4A), —NR^(4B)C(O)R^(4D), —NR^(4B)C(O)OR^(4D),—NR^(4B)OR^(4D), —OCX^(4.1) ₃, —OCHX^(4.1) ₂ (e.g. hydrogen, halogen,—CF₃, —CCl₃, —CBr₃, —CI₃, —CN, —OH, —NH₂, —COOH, —CONH₂, —NO₂, —SH,—SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂, —ONH₂, —NHC(O)NHNH₂, —NHC(O)NH₂, —NHSO₂H,—NHC(O)H, —NHC(O)OH, —NHOH, —OCF₃, —OCCl₃, —OCBr₃, —OCI₃, —OCHF₂,—OCHCl₂, —OCHBr₂, —OCHI₂), R^(4E)-substituted or unsubstituted C₁-C₆alkyl, R^(4E)-substituted or unsubstituted 2 to 6 membered heteroalkyl,R^(4E)-substituted or unsubstituted C₃-C₆ cycloalkyl, R^(4E)-substitutedor unsubstituted 3 to 6 membered heterocycloalkyl, R^(4E)-substituted orunsubstituted phenyl, or R^(4E)-substituted or unsubstituted 5 to 6membered heteroaryl. In embodiments, R⁴ is unsubstituted 2 to 6 memberedheteroalkyl. In embodiments, R⁴ is unsubstituted C₁-C₃ alkoxy. Inembodiments, R⁴ is —OCH₃ or —OCH₂CH₃. In embodiments, R⁴ is hydrogen orunsubstituted or substituted C₁-C₃ alkyl. In embodiments, R⁴ is hydrogenor unsubstituted C₁-C₃ alkyl. In embodiments, R⁴ is hydrogen, methyl orethyl. In embodiments, R⁴ is hydrogen.

R^(4E) is independently oxo, halogen, —CF₃, —CCl₃, —CBr₃, —CI₃, —CN,—OH, —NH₂, —COOH, —CONH₂, —NO₂, —SH, —SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂,—ONH₂, —NHC(O)NHNH₂, —NHC(O)NH₂, —NHSO₂H, —NHC(O)H, —NHC(O)OH, —NHOH,—OCF₃, —OCCl₃, —OCBr₃, —OCI₃, —OCHF₂, —OCHCI₂, —OCHBr₂, —OCHI₂,R^(4F)-substituted or unsubstituted alkyl, R^(4F)-substituted orunsubstituted heteroalkyl, R^(4F)-substituted or unsubstitutedcycloalkyl, R^(4F)-substituted or unsubstituted heterocycloalkyl,R^(4F)-substituted or unsubstituted aryl, or R^(4F)-substituted orunsubstituted heteroaryl. In embodiments, R^(4E) is independently oxo,halogen, —CF₃, —CCl₃, —CBr₃, —CI₃, —CN, —OH, —NH₂, —COOH, —CONH₂, —NO₂,—SH, —SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂, —ONH₂, —NHC(O)NHNH₂, —NHC(O)NH₂,—NHSO₂H, —NHC(O)H, —NHC(O)OH, —NHOH, —OCF₃, —OCCl₃, —OCBr₃, —OCI₃,—OCHF₂, —OCHCl₂, —OCHBr₂, —OCHI₂, R^(4F)-substituted or unsubstitutedC₁-C₆ alkyl, R^(4F)-substituted or unsubstituted 2 to 6 memberedheteroalkyl, R^(4F)-substituted or unsubstituted C₃-C₆ cycloalkyl,R^(4F)-substituted or unsubstituted 3 to 6 membered heterocycloalkyl,R^(4F)-substituted or unsubstituted phenyl, or R^(4F)-substituted orunsubstituted 5 to 6 membered heteroaryl.

In embodiments, R⁵ is independently hydrogen, halogen, —CX^(5.1) ₃,—CHX^(5.1) ₂, —CH₂X^(5.1), —CN, —SO_(n5)R^(5A), —SO_(v5)NR^(5B)R^(5C),—NHNR^(5B)R^(5C), —ONR^(5B)R^(5C), —NHC(O)NHNR^(5B)R^(5C),—NHC(O)NR^(5B)R^(5C), —N(O)_(m5), —NR^(5B)R^(5C), —C(O)R^(5D),—C(O)OR^(5D), —C(O)NR^(5B)R^(5C), —OR^(5A), —NR^(5B)SO₂R^(5A),—NR^(5B)C(O)R^(5D), —NR^(5B)C(O)OR^(5D), —NR^(5B)OR^(5D), —OCX^(5.1) ₃,—OCHX^(5.1) ₂ (e.g. hydrogen, halogen, —CF₃, —CCl₃, —CBr₃, —CI₃, —CN,—OH, —NH₂, —COOH, —CONH₂, —NO₂, —SH, —SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂,—ONH₂, —NHC(O)NHNH₂, —NHC(O)NH₂, —NHSO₂H, —NHC(O)H, —NHC(O)OH, —NHOH,—OCF₃, —OCCl₃, —OCBr₃, —OCI₃, —OCHF₂, —OCHCl₂, —OCHBr₂, —OCHI₂),R^(5E)-substituted or unsubstituted alkyl, R^(5E)-substituted orunsubstituted heteroalkyl, R^(5E)-substituted or unsubstitutedcycloalkyl, R^(5E)-substituted or unsubstituted heterocycloalkyl,R^(5E)-substituted or unsubstituted aryl, or R^(5E)-substituted orunsubstituted heteroaryl. In embodiments, R⁵ is independently hydrogen,halogen, —CX^(5.1) ₃, —CHX^(5.1) ₂, —CH₂X^(5.1), —CN, —SO_(n5)R^(5A),—SO_(v5)NR^(5B)R^(5C), —NHNR^(5B)R^(5C), —ONR^(5B)R^(5C),—NHC(O)NHNR^(5B)R^(5C), —NHC(O)NR^(5B)R^(5C), —N(O)_(m5),—NR^(5B)R^(5C), —C(O)R^(5D), —C(O)OR^(5D), —C(O)NR^(5B)R^(5C), —OR^(5A),—NR^(5B)SO₂R^(5A), —NR^(5B)C(O)R^(5D), —NR^(5B)C(O)OR^(5D),—NR^(5B)OR^(5D), —OCX^(5.1) ₃, —OCHX^(5.1) ₂ (e.g. hydrogen, halogen,—CF₃, —CCl₃, —CBr₃, —CI₃, —CN, —OH, —NH₂, —COOH, —CONH₂, —NO₂, —SH,—SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂, —ONH₂, —NHC(O)NHNH₂, —NHC(O)NH₂, —NHSO₂H,—NHC(O)H, —NHC(O)OH, —NHOH, —OCF₃, —OCCl₃, —OCBr₃, —OCI₃, —OCHF₂,—OCHCl₂, —OCHBr₂, —OCHI₂), R^(5E)-substituted or unsubstituted C₁-C₆alkyl, R^(5E)-substituted or unsubstituted 2 to 6 membered heteroalkyl,R^(5E)-substituted or unsubstituted C₃-C₆ cycloalkyl, R^(5E)-substitutedor unsubstituted 3 to 6 membered heterocycloalkyl, R^(5E)-substituted orunsubstituted phenyl, or R^(5E)-substituted or unsubstituted 5 to 6membered heteroaryl. In embodiments, R⁵ is unsubstituted 2 to 6 memberedheteroalkyl. In embodiments, R⁵ is unsubstituted C₁-C₃ alkoxy. Inembodiments, R⁵ is —OCH₃ or —OCH₂CH₃. In embodiments, R⁵ is hydrogen orunsubstituted or substituted C₁-C₃ alkyl. In embodiments, R⁵ is hydrogenor unsubstituted C₁-C₃ alkyl. In embodiments, R⁵ is hydrogen, methyl orethyl. In embodiments, R⁵ is hydrogen.

R^(5E) is independently oxo, halogen, —CF₃, —CCl₃, —CBr₃, —CI₃, —CN,—OH, —NH₂, —COOH, —CONH₂, —NO₂, —SH, —SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂,—ONH₂, —NHC(O)NHNH₂, —NHC(O)NH₂, —NHSO₂H, —NHC(O)H, —NHC(O)OH, —NHOH,—OCF₃, —OCCl₃, —OCBr₃, —OCI₃, —OCHF₂, —OCHCl₂, —OCHBr₂, —OCHI₂,R^(5F)-substituted or unsubstituted alkyl, R^(5F)-substituted orunsubstituted heteroalkyl, R^(5F)-substituted or unsubstitutedcycloalkyl, R^(5F)-substituted or unsubstituted heterocycloalkyl,R^(5F)-substituted or unsubstituted aryl, or R^(5F)-substituted orunsubstituted heteroaryl. In embodiments, R^(5E) is independently oxo,halogen, —CF₃, —CCl₃, —CBr₃, —CI₃, —CN, —OH, —NH₂, —COOH, —CONH₂, —NO₂,—SH, —SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂, —ONH₂, —NHC(O)NHNH₂, —NHC(O)NH₂,—NHSO₂H, —NHC(O)H, —NHC(O)OH, —NHOH, —OCF₃, —OCCl₃, —OCBr₃, —OCI₃,—OCHF₂, —OCHCl₂, —OCHBr₂, —OCHI₂, R^(5F)-substituted or unsubstitutedC₁-C₆ alkyl, R^(5F)-substituted or unsubstituted 2 to 6 memberedheteroalkyl, R^(5F)-substituted or unsubstituted C₃-C₆ cycloalkyl,R^(5F)-substituted or unsubstituted 3 to 6 membered heterocycloalkyl,R^(5F)-substituted or unsubstituted phenyl, or R^(5F)-substituted orunsubstituted 5 to 6 membered heteroaryl.

In embodiments, R⁶ is independently hydrogen, halogen, —CX^(6.1) ₃,—CHX^(6.1) ₂, —CH₂X^(6.1), —CN, —SO_(n6)R^(6A), —SO_(v6)NR^(6B)R^(6C),—NHNR^(6B)R^(6C), —ONR^(6B)R^(6C), —NHC(O)NHNR^(6B)R^(6C),—NHC(O)NR^(6B)R^(6C), —N(O)_(m6), —NR^(6B)R^(6C), —C(O)R^(6D),—C(O)OR^(6D), —C(O)NR^(6B)R^(6C), —OR^(6A), —NR^(6B)SO₂R^(6A),—NR^(6B)C(O)R^(6D), —NR^(6B)C(O)OR^(6D), —NR^(6B)OR^(6D), —OCX^(6.1) ₃,—OCHX^(6.1) ₂ (e.g. hydrogen, halogen, —CF₃, —CCl₃, —CBr₃, —CI₃, —CN,—OH, —NH₂, —COOH, —CONH₂, —NO₂, —SH, —SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂,—ONH₂, —NHC(O)NHNH₂, —NHC(O)NH₂, —NHSO₂H, —NHC(O)H, —NHC(O)OH, —NHOH,—OCF₃, —OCCl₃, —OCBr₃, —OCI₃, —OCHF₂, —OCHCl₂, —OCHBr₂, —OCHI₂),R^(6E)-substituted or unsubstituted alkyl, R^(6E)-substituted orunsubstituted heteroalkyl, R^(6E)-substituted or unsubstitutedcycloalkyl, R^(6E)-substituted or unsubstituted heterocycloalkyl,R^(6E)-substituted or unsubstituted aryl, or R^(6E)-substituted orunsubstituted heteroaryl. In embodiments, R⁶ is independently hydrogen,halogen, —CF₃, —CCl₃, —CBr₃, —CI₃, —CN, —OH, —NH₂, —COOH, —CONH₂, —NO₂,—SH, —SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂, —ONH₂, —NHC(O)NHNH₂, —NHC(O)NH₂,—NHSO₂H, —NHC(O)H, —NHC(O)OH, —NHOH, —OCF₃, —OCCl₃, —OCBr₃, —OCI₃,—OCHF₂, —OCHCl₂, —OCHBr₂, —OCHI₂), R^(6E)-substituted or unsubstitutedC₁-C₆ alkyl, R^(6E)-substituted or unsubstituted 2 to 6 memberedheteroalkyl, R^(6E)-substituted or unsubstituted C₃-C₆ cycloalkyl,R^(6E)-substituted or unsubstituted 3 to 6 membered heterocycloalkyl,R^(6E)-substituted or unsubstituted phenyl, or R^(6E)-substituted orunsubstituted 5 to 6 membered heteroaryl. In embodiments, R⁶ isunsubstituted alkoxy. In embodiments, R⁶ is unsubstituted C₁-C₃ alkoxy.In embodiments, R⁶ is —OCH₃ or —OCH₂CH₃. In embodiments, R⁶ is —OCH₂CH₃.In embodiments, R⁶ is halogen. In embodiments, R⁶ is chlorine orfluorine.

R^(6E) is independently oxo, halogen, —CF₃, —CCl₃, —CBr₃, —CI₃, —CN,—OH, —NH₂, —COOH, —CONH₂, —NO₂, —SH, —SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂,—ONH₂, —NHC(O)NHNH₂, —NHC(O)NH₂, —NHSO₂H, —NHC(O)H, —NHC(O)OH, —NHOH,—OCF₃, —OCCl₃, —OCBr₃, —OCI₃, —OCHF₂, —OCHCl₂, —OCHBr₂, —OCHI₂,R^(6F)-substituted or unsubstituted alkyl, R^(6F)-substituted orunsubstituted heteroalkyl, R^(6F)-substituted or unsubstitutedcycloalkyl, R^(6F)-substituted or unsubstituted heterocycloalkyl,R^(6F)-substituted or unsubstituted aryl, or R^(6F)-substituted orunsubstituted heteroaryl. In embodiments, R^(6E) is independently oxo,halogen, —CF₃, —CCl₃, —CBr₃, —CI₃, —CN, —OH, —NH₂, —COOH, —CONH₂, —NO₂,—SH, —SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂, —ONH₂, —NHC(O)NHNH₂, —NHC(O)NH₂,—NHSO₂H, —NHC(O)H, —NHC(O)OH, —NHOH, —OCF₃, —OCCl₃, —OCBr₃, —OCI₃,—OCHF₂, —OCHCl₂, —OCHBr₂, —OCHI₂, R^(6F)-substituted or unsubstitutedC₁-C₆ alkyl, R^(6F)-substituted or unsubstituted 2 to 6 memberedheteroalkyl, R^(6F)-substituted or unsubstituted C₃-C₆ cycloalkyl,R^(6F)-substituted or unsubstituted 3 to 6 membered heterocycloalkyl,R^(6F)-substituted or unsubstituted phenyl, or R^(6F)-substituted orunsubstituted 5 to 6 membered heteroaryl.

In embodiments, R⁷ is independently hydrogen, halogen, —CX^(7.1) ₃,—CHX^(7.1) ₂, —CH₂X^(7.1), —CN, —SO_(n7)R^(7A), —SO_(v7)NR^(7B)R^(7C),—NHNR^(7B)R^(7C), —ONR^(7B)R^(7C), —NHC(O)NHNR^(7B)R^(7C),—NHC(O)NR^(7B)R^(7C), —N(O)_(m7), —NR^(7B)R^(7C), —C(O)R^(7D),—C(O)OR^(7D), —C(O)NR^(7B)R^(7C), —OR^(7A), —NR^(7B)SO₂R^(7A),—NR^(7B)C(O)R^(7D), —NR^(7B)C(O)OR^(7D), —NR^(7B)OR^(7D), —OCX^(7.1) ₃,—OCHX^(7.1) ₂ (e.g. hydrogen, halogen, —CF₃, —CCl₃, —CBr₃, —CI₃, —CN,—OH, —NH₂, —COOH, —CONH₂, —NO₂, —SH, —SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂,—ONH₂, —NHC(O)NHNH₂, —NHC(O)NH₂, —NHSO₂H, —NHC(O)H, —NHC(O)OH, —NHOH,—OCF₃, —OCCl₃, —OCBr₃, —OCI₃, —OCHF₂, —OCHCl₂, —OCHBr₂, —OCHI₂),R^(7E)-substituted or unsubstituted alkyl, R^(7E)-substituted orunsubstituted heteroalkyl, R^(7E)-substituted or unsubstitutedcycloalkyl, R^(7E)-substituted or unsubstituted heterocycloalkyl,R^(7E)-substituted or unsubstituted aryl, or R^(7E)-substituted orunsubstituted heteroaryl. In embodiments, R⁷ is independently hydrogen,halogen, —CF₃, —CCl₃, —CBr₃, —CI₃, —CN, —OH, —NH₂, —COOH, —CONH₂, —NO₂,—SH, —SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂, —ONH₂, —NHC(O)NHNH₂, —NHC(O)NH₂,—NHSO₂H, —NHC(O)H, —NHC(O)OH, —NHOH, —OCF₃, —OCCl₃, —OCBr₃, —OCI₃,—OCHF₂, —OCHCl₂, —OCHBr₂, —OCHI₂), R^(7E)-substituted or unsubstitutedC₁-C₆ alkyl, R^(7E)-substituted or unsubstituted 2 to 6 memberedheteroalkyl, R^(7E)-substituted or unsubstituted C₃-C₆ cycloalkyl,R^(7E)-substituted or unsubstituted 3 to 6 membered heterocycloalkyl,R^(7E)-substituted or unsubstituted phenyl, or R^(7E)-substituted orunsubstituted 5 to 6 membered heteroaryl. In embodiments, R⁷ is halogen.In embodiments, R⁷ is chlorine or fluorine.

R^(7E) is independently oxo, halogen, —CF₃, —CCl₃, —CBr₃, —CI₃, —CN,—OH, —NH₂, —COOH, —CONH₂, —NO₂, —SH, —SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂,—ONH₂, —NHC(O)NHNH₂, —NHC(O)NH₂, —NHSO₂H, —NHC(O)H, —NHC(O)OH, —NHOH,—OCF₃, —OCCl₃, —OCBr₃, —OCI₃, —OCHF₂, —OCHCl₂, —OCHBr₂, —OCHI₂,R^(7F)-substituted or unsubstituted alkyl, R^(7F)-substituted orunsubstituted heteroalkyl, R^(7F)-substituted or unsubstitutedcycloalkyl, R^(7F)-substituted or unsubstituted heterocycloalkyl,R^(7F)-substituted or unsubstituted aryl, or R^(7F)-substituted orunsubstituted heteroaryl. In embodiments, R^(7E) is independently oxo,halogen, —CF₃, —CCl₃, —CBr₃, —CI₃, —CN, —OH, —NH₂, —COOH, —CONH₂, —NO₂,—SH, —SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂, —ONH₂, —NHC(O)NHNH₂, —NHC(O)NH₂,—NHSO₂H, —NHC(O)H, —NHC(O)OH, —NHOH, —OCF₃, —OCCl₃, —OCBr₃, —OCI₃,—OCHF₂, —OCHCl₂, —OCHBr₂, —OCHI₂, R^(7F)-substituted or unsubstitutedC₁-C₆ alkyl, R^(7F)-substituted or unsubstituted 2 to 6 memberedheteroalkyl, R^(7F)-substituted or unsubstituted C₃-C₆ cycloalkyl,R^(7F)-substituted or unsubstituted 3 to 6 membered heterocycloalkyl,R^(7F)-substituted or unsubstituted phenyl, or R^(7F)-substituted orunsubstituted 5 to 6 membered heteroaryl.

In embodiments, R⁸ is independently hydrogen, halogen, —CX^(8.1) ₃,—CHX^(8.1) ₂, —CH₂X^(8.1), —CN, —SO_(n8)R^(8A), —SO_(v8)NR^(8B)R^(8C),—NHNR^(8B)R^(8C), —ONR^(8B)R^(8C), —NHC(O)NHNR^(8B)R^(8C),—NHC(O)NR^(8B)R^(8C), —N(O)_(m8), —NR^(8B)R^(8C), —C(O)R^(8D),—C(O)OR^(8D), —C(O)NR^(8B)R^(8C), —OR^(8A), —NR^(8B)SO₂R^(8A),—NR^(8B)C(O)R^(8D), —NR^(8B)C(O)OR^(8D), —NR^(8B)OR^(8D), —OCX^(8.1) ₃,—OCHX^(8.1) ₂ (e.g. hydrogen, halogen, —CF₃, —CCl₃, —CBr₃, —CI₃, —CN,—OH, —NH₂, —COOH, —CONH₂, —NO₂, —SH, —SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂,—ONH₂, —NHC(O)NHNH₂, —NHC(O)NH₂, —NHSO₂H, —NHC(O)H, —NHC(O)OH, —NHOH,—OCF₃, —OCCl₃, —OCBr₃, —OCI₃, —OCHF₂, —OCHCl₂, —OCHBr₂, —OCHI₂),R^(8E)-substituted or unsubstituted alkyl, R^(8E)-substituted orunsubstituted heteroalkyl, R^(8E)-substituted or unsubstitutedcycloalkyl, R^(8E)-substituted or unsubstituted heterocycloalkyl,R^(8E)-substituted or unsubstituted aryl, or R^(8E)-substituted orunsubstituted heteroaryl. In embodiments, R⁸ is independently hydrogen,halogen, —CX^(5.1) ₃, —CHX^(5.1) ₂, —CH₂X^(5.1), —CN, —SO_(n5)R^(5A),—SO_(v5)NR^(5B)R^(5C), —NHNR^(5B)R^(5C), —ONR^(5B)R^(5C),—NHC(O)NHNR^(5B)R^(5C), —NHC(O)NR^(5B)R^(5C), —N(O)_(m5),—NR^(5B)R^(5C), —C(O)R^(5D), —C(O)OR^(5D), —C(O)NR^(5B)R^(5C), —OR^(5A),—NR^(5B)SO₂R^(5A), —NR^(5B)C(O)R^(5D), —NR^(5B)C(O)OR^(5D),—NR^(5B)OR^(5D), —OCX^(5.1) ₃, —OCHX^(5.1) ₂ (e.g. hydrogen, halogen,—CF₃, —CCl₃, —CBr₃, —CI₃, —CN, —OH, —NH₂, —COOH, —CONH₂, —NO₂, —SH,—SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂, —ONH₂, —NHC(O)NHNH₂, —NHC(O)NH₂, —NHSO₂H,—NHC(O)H, —NHC(O)OH, —NHOH, —OCF₃, —OCCl₃, —OCBr₃, —OCI₃, —OCHF₂,—OCHCl₂, —OCHBr₂, —OCHI₂), R^(8E)-substituted or unsubstituted C₁-C₆alkyl, R^(8E)-substituted or unsubstituted 2 to 6 membered heteroalkyl,R^(8E)-substituted or unsubstituted C₃-C₆ cycloalkyl, R^(8E)-substitutedor unsubstituted 3 to 6 membered heterocycloalkyl, R^(8E)-substituted orunsubstituted phenyl, or R^(8E)-substituted or unsubstituted 5 to 6membered heteroaryl. In embodiments, R⁸ is halogen. In embodiments, R⁸is chlorine or fluorine.

R^(8E) is independently oxo, halogen, —CF₃, —CCl₃, —CBr₃, —CI₃, —CN,—OH, —NH₂, —COOH, —CONH₂, —NO₂, —SH, —SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂,—ONH₂, —NHC(O)NHNH₂, —NHC(O)NH₂, —NHSO₂H, —NHC(O)H, —NHC(O)OH, —NHOH,—OCF₃, —OCCl₃, —OCBr₃, —OCI₃, —OCHF₂, —OCHCl₂, —OCHBr₂, —OCHI₂,R^(8F)-substituted or unsubstituted alkyl, R^(8F)-substituted orunsubstituted heteroalkyl, R^(8F)-substituted or unsubstitutedcycloalkyl, R^(8F)-substituted or unsubstituted heterocycloalkyl,R^(8F)-substituted or unsubstituted aryl, or R^(8F)-substituted orunsubstituted heteroaryl. In embodiments, R^(8E) is independently oxo,halogen, —CF₃, —CCl₃, —CBr₃, —CI₃, —CN, —OH, —NH₂, —COOH, —CONH₂, —NO₂,—SH, —SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂, —ONH₂, —NHC(O)NHNH₂, —NHC(O)NH₂,—NHSO₂H, —NHC(O)H, —NHC(O)OH, —NHOH, —OCF₃, —OCCl₃, —OCBr₃, —OCI₃,—OCHF₂, —OCHCl₂, —OCHBr₂, —OCHI₂, R^(8F)-substituted or unsubstitutedC₁-C₆ alkyl, R^(8F)-substituted or unsubstituted 2 to 6 memberedheteroalkyl, R^(8F)-substituted or unsubstituted C₃-C₆ cycloalkyl,R^(8F)-substituted or unsubstituted 3 to 6 membered heterocycloalkyl,R^(8F)-substituted or unsubstituted phenyl, or R^(8F)-substituted orunsubstituted 5 to 6 membered heteroaryl.

In embodiments, R⁹ is independently hydrogen, halogen, —CX^(9.1) ₃,—CHX^(9.1) ₂, —CH₂X^(9.1), —CN, —SO_(n9)R^(9A), —SO_(v9)NR^(9B)R^(9C),—NHNR^(9B)R^(9C), —ONR^(9B)R^(9C), —NHC(O)NHNR^(9B)R^(9C),—NHC(O)NR^(9B)R^(9C), —N(O)_(m9), —NR^(9B)R^(9C), —C(O)R^(9D),—C(O)OR^(9D), —C(O)NR^(9B)R^(9C), —OR^(9A), —NR^(9B)SO₂R^(9A),—NR^(9B)C(O)R^(9D), —NR^(9B)C(O)OR^(9D), —NR^(9B)OR^(9D), —OCX^(9.1) ₃,—OCHX^(9.1) ₂ (e.g. hydrogen, halogen, —CF₃, —CCl₃, —CBr₃, —CI₃, —CN,—OH, —NH₂, —COOH, —CONH₂, —NO₂, —SH, —SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂,—ONH₂, —NHC(O)NHNH₂, —NHC(O)NH₂, —NHSO₂H, —NHC(O)H, —NHC(O)OH, —NHOH,—OCF₃, —OCCl₃, —OCBr₃, —OCI₃, —OCHF₂, —OCHCl₂, —OCHBr₂, —OCHI₂),R^(9E)-substituted or unsubstituted alkyl, R^(9E)-substituted orunsubstituted heteroalkyl, R^(9E)-substituted or unsubstitutedcycloalkyl, R^(9E)-substituted or unsubstituted heterocycloalkyl,R^(9E)-substituted or unsubstituted aryl, or R^(9E)-substituted orunsubstituted heteroaryl. In embodiments, R⁹ is independently hydrogen,halogen, —CX^(9.1) ₃, —CHX^(5.1) ₂, —CH₂X^(9.1), —CN, —SO_(n9)R^(9A),—SO_(v9)NR^(9B)R^(9C), —NHNR^(9B)R^(9C), —ONR^(9B)R^(9C),—NHC(O)NHNR^(9B)R^(9C), —NHC(O)NR^(9B)R^(9C), —N(O)_(m9),—NR^(9B)R^(9C), —C(O)R^(9D), —C(O)OR^(9D), —C(O)NR^(9B)R^(9C), —OR^(9A),—NR^(9B)SO₂R^(9A), —NR^(9B)C(O)R^(9D), —NR^(9B)C(O)OR^(9D),—NR^(9B)OR^(9D), —OCX^(9.1) ₃, —OCHX^(9.l) ₂ (e.g. hydrogen, halogen,—CF₃, —CCl₃, —CBr₃, —CI₃, —CN, —OH, —NH₂, —COOH, —CONH₂, —NO₂, —SH,—SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂, —ONH₂, —NHC(O)NHNH₂, —NHC(O)NH₂, —NHSO₂H,—NHC(O)H, —NHC(O)OH, —NHOH, —OCF₃, —OCCl₃, —OCBr₃, —OCI₃, —OCHF₂,—OCHCl₂, —OCHBr₂, —OCHI₂), R^(9E)-substituted or unsubstituted C₁-C₆alkyl, R^(9E)-substituted or unsubstituted 2 to 6 membered heteroalkyl,R^(9E)-substituted or unsubstituted C₃-C₆ cycloalkyl, R^(9E)-substitutedor unsubstituted 3 to 6 membered heterocycloalkyl, R^(9E)-substituted orunsubstituted phenyl, or R^(9E)-substituted or unsubstituted 5 to 6membered heteroaryl.

R^(9E) is independently oxo, halogen, —CF₃, —CCl₃, —CBr₃, —CI₃, —CN,—OH, —NH₂, —COOH, —CONH₂, —NO₂, —SH, —SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂,—ONH₂, —NHC(O)NHNH₂, —NHC(O)NH₂, —NHSO₂H, —NHC(O)H, —NHC(O)OH, —NHOH,—OCF₃, —OCCl₃, —OCBr₃, —OCI₃, —OCHF₂, —OCHCl₂, —OCHBr₂, —OCHI₂,R^(9F)-substituted or unsubstituted alkyl, R^(9F)-substituted orunsubstituted heteroalkyl, R^(9F)-substituted or unsubstitutedcycloalkyl, R^(9F)-substituted or unsubstituted heterocycloalkyl,R^(9F)-substituted or unsubstituted aryl, or R^(9F)-substituted orunsubstituted heteroaryl. In embodiments, R^(9E) is independently oxo,halogen, —CF₃, —CCl₃, —CBr₃, —CI₃, —CN, —OH, —NH₂, —COOH, —CONH₂, —NO₂,—SH, —SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂, —ONH₂, —NHC(O)NHNH₂, —NHC(O)NH₂,—NHSO₂H, —NHC(O)H, —NHC(O)OH, —NHOH, —OCF₃, —OCCl₃, —OCBr₃, —OCI₃,—OCHF₂, —OCHCl₂, —OCHBr₂, —OCHI₂, R^(9F)-substituted or unsubstitutedC₁-C₆ alkyl, R^(9F)-substituted or unsubstituted 2 to 6 memberedheteroalkyl, R^(9F)-substituted or unsubstituted C₃-C₆ cycloalkyl,R^(9F)-substituted or unsubstituted 3 to 6 membered heterocycloalkyl,R^(9F)-substituted or unsubstituted phenyl, or R^(9F)-substituted orunsubstituted 5 to 6 membered heteroaryl.

In embodiments, R¹⁰ is independently hydrogen, halogen, —CX^(10.1) ₃,—CHX^(10.1) ₂, —CH₂X^(10.1), —CN, —SO_(n10)R^(10A),—SO_(v10)NR^(10B)R^(10C), —NHNR^(10B)R^(10C), —ONR^(10B)R^(10C),—NHC(O)NHNR^(10B)R^(10C), —NHC(O)NR^(10B)R^(10C), —N(O)_(m10),—NR^(10B)R^(10C), —C(O)R^(10D), —C(O)OR^(10D), —C(O)NR^(10B)R^(10C),—OR^(10A), —NR^(10B)SO₂R^(10A), —NR^(10B)C(O)R^(10D),—NR^(10B)C(O)OR^(10D), —NR^(10B)OR^(10D), —OCX^(10′), —OCHX^(10.1) ₂(e.g. hydrogen, halogen, —CF₃, —CCl₃, —CBr₃, —CI₃, —CN, —OH, —NH₂,—COOH, —CONH₂, —NO₂, —SH, —SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂, —ONH₂,—NHC(O)NHNH₂, —NHC(O)NH₂, —NHSO₂H, —NHC(O)H, —NHC(O)OH, —NHOH, —OCF₃,—OCCl₃, —OCBr₃, —OCI₃, —OCHF₂, —OCHCl₂, —OCHBr₂, —OCHI₂),R^(10E)-substituted or unsubstituted alkyl, R^(10E)-substituted orunsubstituted heteroalkyl, R^(10E)-substituted or unsubstitutedcycloalkyl, R^(10E)-substituted or unsubstituted heterocycloalkyl,R^(10E)-substituted or unsubstituted aryl, or R^(10E)-substituted orunsubstituted heteroaryl. In embodiments, R¹⁰ is independently hydrogen,halogen, —CX^(10.1) ₃, —CHX^(10.1) ₂, —CH₂X^(10.1), —CN,—SO_(n10)R^(10A), —SO_(v10)NR^(10B)R^(10C), —NHNR^(10B)R^(10C),—ONR^(10B)R^(10C), —NHC(O)NHNR^(10B)R^(10C), —NHC(O)NR^(10B)R^(10C),—N(O)_(m10), —NR^(10B)R^(10C), —C(O)R^(10D), —C(O)OR^(10D),—C(O)NR^(10B)R^(10C), —OR^(10A), —NR^(10B)SO₂R^(10A),—NR^(10B)C(O)R^(10D), —NR^(10B)C(O)OR^(10D), —NR^(10B)OR^(10D),—OCX^(10′), —OCHX^(10.1) ₂ (e.g. hydrogen, halogen, —CF₃, —CCl₃, —CBr₃,—CI₃, —CN, —OH, —NH₂, —COOH, —CONH₂, —NO₂, —SH, —SO₃H, —SO₄H, —SO₂NH₂,—NHNH₂, —ONH₂, —NHC(O)NHNH₂, —NHC(O)NH₂, —NHSO₂H, —NHC(O)H, —NHC(O)OH,—NHOH, —OCF₃, —OCCl₃, —OCBr₃, —OCI₃, —OCHF₂, —OCHCl₂, —OCHBr₂, —OCHI₂),R^(10E)-substituted or unsubstituted C₁-C₆ alkyl, R^(10E)-substituted orunsubstituted 2 to 6 membered heteroalkyl, R^(10E)-substituted orunsubstituted C₃-C₆ cycloalkyl, R^(10E)-substituted or unsubstituted 3to 6 membered heterocycloalkyl, R^(10E)-substituted or unsubstitutedphenyl, or R^(10E)-substituted or unsubstituted 5 to 6 memberedheteroaryl.

R^(10E) is independently oxo, halogen, —CF₃, —CCl₃, —CBr₃, —CI₃, —CN,—OH, —NH₂, —COOH, —CONH₂, —NO₂, —SH, —SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂,—ONH₂, —NHC(O)NHNH₂, —NHC(O)NH₂, —NHSO₂H, —NHC(O)H, —NHC(O)OH, —NHOH,—OCF₃, —OCCl₃, —OCBr₃, —OCI₃, —OCHF₂, —OCHCl₂, —OCHBr₂, —OCHI₂,R^(10F)-substituted or unsubstituted alkyl, R^(10F)-substituted orunsubstituted heteroalkyl, R^(10F)-substituted or unsubstitutedcycloalkyl, R^(10F)-substituted or unsubstituted heterocycloalkyl,R^(10F)-substituted or unsubstituted aryl, or R^(10F)-substituted orunsubstituted heteroaryl. In embodiments, R^(10E) is independently oxo,halogen, —CF₃, —CCl₃, —CBr₃, —CI₃, —CN, —OH, —NH₂, —COOH, —CONH₂, —NO₂,—SH, —SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂, —ONH₂, —NHC(O)NHNH₂, —NHC(O)NH₂,—NHSO₂H, —NHC(O)H, —NHC(O)OH, —NHOH, —OCF₃, —OCCl₃, —OCBr₃, —OCI₃,—OCHF₂, —OCHCl₂, —OCHBr₂, —OCHI₂, R^(10F)-substituted or unsubstitutedC₁-C₆ alkyl, R^(10F)-substituted or unsubstituted 2 to 6 memberedheteroalkyl, R^(10F)-substituted or unsubstituted C₃-C₆ cycloalkyl,R^(10F)-substituted or unsubstituted 3 to 6 membered heterocycloalkyl,R^(10F)-substituted or unsubstituted phenyl, or R^(10F)-substituted orunsubstituted 5 to 6 membered heteroaryl.

In embodiments, R^(1A) is independently hydrogen, halogen, —CF₃, —CCl₃,—CBr₃, —CI₃, —CN, —OH, —NH₂, —COOH, —CONH₂, —NO₂, —SH, —SO₃H, —SO₄H,—SO₂NH₂, —NHNH₂, —ONH₂, —NHC(O)NHNH₂, —NHC(O)NH₂, —NHSO₂H, —NHC(O)H,—NHC(O)OH, —NHOH, —OCF₃, —OCCl₃, —OCBr₃, —OCI₃, —OCHF₂, —OCHCl₂,—OCHBr₂, —OCHI₂, R^(10F)-substituted or unsubstituted alkyl,R^(1AF)-substituted or unsubstituted heteroalkyl, R^(1AF)-substituted orunsubstituted cycloalkyl, R^(1AF)-substituted or unsubstitutedheterocycloalkyl, R^(1AF)-substituted or unsubstituted aryl, orR^(1AF)-substituted or unsubstituted heteroaryl. In embodiments, R^(1AF)is independently hydrogen, halogen, —CF₃, —CCl₃, —CBr₃, —CI₃, —CN, —OH,—NH₂, —COOH, —CONH₂, —NO₂, —SH, —SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂, —ONH₂,—NHC(O)NHNH₂, —NHC(O)NH₂, —NHSO₂H, —NHC(O)H, —NHC(O)OH, —NHOH, —OCF₃,—OCCl₃, —OCBr₃, —OCI₃, —OCHF₂, —OCHCl₂, —OCHBr₂, —OCHI₂,R^(1AF)-substituted or unsubstituted C₁-C₆ alkyl, R^(1AF)-substituted orunsubstituted 2 to 6 membered heteroalkyl, R^(1AF)-substituted orunsubstituted C₃-C₆ cycloalkyl, R^(1AF)-substituted or unsubstituted 3to 6 membered heterocycloalkyl, R^(1AF)-substituted or unsubstitutedphenyl, or R^(1AF)-substituted or unsubstituted 5 to 6 memberedheteroaryl.

In embodiments, R^(1B) is independently hydrogen, halogen, —CF₃, —CCl₃,—CBr₃, —CI₃, —CN, —OH, —NH₂, —COOH, —CONH₂, —NO₂, —SH, —SO₃H, —SO₄H,—SO₂NH₂, —NHNH₂, —ONH₂, —NHC(O)NHNH₂, —NHC(O)NH₂, —NHSO₂H, —NHC(O)H,—NHC(O)OH, —NHOH, —OCF₃, —OCCl₃, —OCBr₃, —OCI₃, —OCHF₂, —OCHCl₂,—OCHBr₂, —OCHI₂, R^(1BF)-substituted or unsubstituted alkyl,R^(1BF)-substituted or unsubstituted heteroalkyl, R^(1BF)-substituted orunsubstituted cycloalkyl, R^(1BF)-substituted or unsubstitutedheterocycloalkyl, R^(1BF)-substituted or unsubstituted aryl, orR^(1BF)-substituted or unsubstituted heteroaryl. In embodiments, R^(1B)is independently hydrogen, halogen, —CF₃, —CCl₃, —CBr₃, —CI₃, —CN, —OH,—NH₂, —COOH, —CONH₂, —NO₂, —SH, —SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂, —ONH₂,—NHC(O)NHNH₂, —NHC(O)NH₂, —NHSO₂H, —NHC(O)H, —NHC(O)OH, —NHOH, —OCF₃,—OCCl₃, —OCBr₃, —OCI₃, —OCHF₂, —OCHCl₂, —OCHBr₂, —OCHI₂,R^(1BF)-substituted or unsubstituted C₁-C₆ alkyl, R^(1BF)-substituted orunsubstituted 2 to 6 membered heteroalkyl, R^(1BF)-substituted orunsubstituted C₃-C₆ cycloalkyl, R^(1BF)-substituted or unsubstituted 3to 6 membered heterocycloalkyl, R^(1BF)-substituted or unsubstitutedphenyl, or R^(1BF)-substituted or unsubstituted 5 to 6 memberedheteroaryl.

In embodiments, R^(1C) is independently hydrogen, halogen, —CF₃, —CCl₃,—CBr₃, —CI₃, —CN, —OH, —NH₂, —COOH, —CONH₂, —NO₂, —SH, —SO₃H, —SO₄H,—SO₂NH₂, —NHNH₂, —ONH₂, —NHC(O)NHNH₂, —NHC(O)NH₂, —NHSO₂H, —NHC(O)H,—NHC(O)OH, —NHOH, —OCF₃, —OCCl₃, —OCBr₃, —OCI₃, —OCHF₂, —OCHCl₂,—OCHBr₂, —OCHI₂, R^(1CF)-substituted or unsubstituted alkyl,R^(1CF)-substituted or unsubstituted heteroalkyl, R^(1CF)-substituted orunsubstituted cycloalkyl, R^(1CF)-substituted or unsubstitutedheterocycloalkyl, R^(1CF)-substituted or unsubstituted aryl, orR^(1CF)-substituted or unsubstituted heteroaryl. In embodiments, R^(1C)is independently hydrogen, halogen, —CF₃, —CCl₃, —CBr₃, —CI₃, —CN, —OH,—NH₂, —COOH, —CONH₂, —NO₂, —SH, —SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂, —ONH₂,—NHC(O)NHNH₂, —NHC(O)NH₂, —NHSO₂H, —NHC(O)H, —NHC(O)OH, —NHOH, —OCF₃,—OCCl₃, —OCBr₃, —OCI₃, —OCHF₂, —OCHCl₂, —OCHBr₂, —OCHI₂,R^(1CF)-substituted or unsubstituted C₁-C₆ alkyl, R^(1CF)-substituted orunsubstituted 2 to 6 membered heteroalkyl, R^(1CF)-substituted orunsubstituted C₃-C₆ cycloalkyl, R^(1CF)-substituted or unsubstituted 3to 6 membered heterocycloalkyl, R^(1CF)-substituted or unsubstitutedphenyl, or R^(1CF)-substituted or unsubstituted 5 to 6 memberedheteroaryl. R^(1B) and R^(1C) bonded to the same nitrogen atom mayoptionally be joined to form a R^(1CF)-substituted or unsubstituted 3 to6 membered heterocycloalkyl or R^(1CF)-substituted or unsubstituted 5 to6 membered heteroaryl.

In embodiments, R^(1D) is independently hydrogen, halogen, —CF₃, —CCl₃,—CBr₃, —CI₃, —CN, —OH, —NH₂, —COOH, —CONH₂, —NO₂, —SH, —SO₃H, —SO₄H,—SO₂NH₂, —NHNH₂, —ONH₂, —NHC(O)NHNH₂, —NHC(O)NH₂, —NHSO₂H, —NHC(O)H,—NHC(O)OH, —NHOH, —OCF₃, —OCCl₃, —OCBr₃, —OCI₃, —OCHF₂, —OCHCl₂,—OCHBr₂, —OCHI₂, R^(1DF)-substituted or unsubstituted alkyl,R^(1DF)-substituted or unsubstituted heteroalkyl, R^(1DF)-substituted orunsubstituted cycloalkyl, R^(1DF)-substituted or unsubstitutedheterocycloalkyl, R^(1DF)-substituted or unsubstituted aryl, orR^(1DF)-substituted or unsubstituted heteroaryl. In embodiments, R^(1D)is independently hydrogen, halogen, —CF₃, —CCl₃, —CBr₃, —CI₃, —CN, —OH,—NH₂, —COOH, —CONH₂, —NO₂, —SH, —SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂, —ONH₂,—NHC(O)NHNH₂, —NHC(O)NH₂, —NHSO₂H, —NHC(O)H, —NHC(O)OH, —NHOH, —OCF₃,—OCCl₃, —OCBr₃, —OCI₃, —OCHF₂, —OCHCl₂, —OCHBr₂, —OCHI₂,R^(1DF)-substituted or unsubstituted C₁-C₆ alkyl, R^(1DF)-substituted orunsubstituted 2 to 6 membered heteroalkyl, R^(1DF)-substituted orunsubstituted C₃-C₆ cycloalkyl, R^(1DF)-substituted or unsubstituted 3to 6 membered heterocycloalkyl, R^(1DF)-substituted or unsubstitutedphenyl, or R^(1DF)-substituted or unsubstituted 5 to 6 memberedheteroaryl.

In embodiments, R^(2A) is independently hydrogen, halogen, —CF₃, —CCl₃,—CBr₃, —CI₃, —CN, —OH, —NH₂, —COOH, —CONH₂, —NO₂, —SH, —SO₃H, —SO₄H,—SO₂NH₂, —NHNH₂, —ONH₂, —NHC(O)NHNH₂, —NHC(O)NH₂, —NHSO₂H, —NHC(O)H,—NHC(O)OH, —NHOH, —OCF₃, —OCCl₃, —OCBr₃, —OCI₃, —OCHF₂, —OCHCl₂,—OCHBr₂, —OCHI₂, R^(2AF)-substituted or unsubstituted alkyl,R^(2AF)-substituted or unsubstituted heteroalkyl, R^(2AF)-substituted orunsubstituted cycloalkyl, R^(2AF)-substituted or unsubstitutedheterocycloalkyl, R^(2AF)-substituted or unsubstituted aryl, orR^(2AF)-substituted or unsubstituted heteroaryl. In embodiments, R^(2A)is independently hydrogen, halogen, —CF₃, —CCl₃, —CBr₃, —CI₃, —CN, —OH,—NH₂, —COOH, —CONH₂, —NO₂, —SH, —SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂, —ONH₂,—NHC(O)NHNH₂, —NHC(O)NH₂, —NHSO₂H, —NHC(O)H, —NHC(O)OH, —NHOH, —OCF₃,—OCCl₃, —OCBr₃, —OCI₃, —OCHF₂, —OCHCl₂, —OCHBr₂, —OCHI₂,R^(2AF)-substituted or unsubstituted C₁-C₆ alkyl, R^(2AF)-substituted orunsubstituted 2 to 6 membered heteroalkyl, R^(2AF)-substituted orunsubstituted C₃-C₆ cycloalkyl, R^(2AF)-substituted or unsubstituted 3to 6 membered heterocycloalkyl, R^(2AF)-substituted or unsubstitutedphenyl, or R^(2AF)-substituted or unsubstituted 5 to 6 memberedheteroaryl.

In embodiments, R^(2B) is independently hydrogen, halogen, —CF₃, —CCl₃,—CBr₃, —CI₃, —CN, —OH, —NH₂, —COOH, —CONH₂, —NO₂, —SH, —SO₃H, —SO₄H,—SO₂NH₂, —NHNH₂, —ONH₂, —NHC(O)NHNH₂, —NHC(O)NH₂, —NHSO₂H, —NHC(O)H,—NHC(O)OH, —NHOH, —OCF₃, —OCCl₃, —OCBr₃, —OCI₃, —OCHF₂, —OCHCl₂,—OCHBr₂, —OCHI₂, R^(2BF)-substituted or unsubstituted alkyl,R^(2BF)-substituted or unsubstituted heteroalkyl, R^(2BF)-substituted orunsubstituted cycloalkyl, R^(2BF)-substituted or unsubstitutedheterocycloalkyl, R^(2BF)-substituted or unsubstituted aryl, orR^(2BF)-substituted or unsubstituted heteroaryl. In embodiments, R^(2B)is independently hydrogen, halogen, —CF₃, —CCl₃, —CBr₃, —CI₃, —CN, —OH,—NH₂, —COOH, —CONH₂, —NO₂, —SH, —SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂, —ONH₂,—NHC(O)NHNH₂, —NHC(O)NH₂, —NHSO₂H, —NHC(O)H, —NHC(O)OH, —NHOH, —OCF₃,—OCCl₃, —OCBr₃, —OCI₃, —OCHF₂, —OCHCl₂, —OCHBr₂, —OCHI₂,R^(2BF)-substituted or unsubstituted C₁-C₆ alkyl, R^(2BF)-substituted orunsubstituted 2 to 6 membered heteroalkyl, R^(2BF)-substituted orunsubstituted C₃-C₆ cycloalkyl, R^(2BF)-substituted or unsubstituted 3to 6 membered heterocycloalkyl, R^(2BF)-substituted or unsubstitutedphenyl, or R^(2B)-substituted or unsubstituted 5 to 6 memberedheteroaryl.

In embodiments, R^(2C) is independently hydrogen, halogen, —CF₃, —CCl₃,—CBr₃, —CI₃, —CN, —OH, —NH₂, —COOH, —CONH₂, —NO₂, —SH, —SO₃H, —SO₄H,—SO₂NH₂, —NHNH₂, —ONH₂, —NHC(O)NHNH₂, —NHC(O)NH₂, —NHSO₂H, —NHC(O)H,—NHC(O)OH, —NHOH, —OCF₃, —OCCl₃, —OCBr₃, —OCI₃, —OCHF₂, —OCHCl₂,—OCHBr₂, —OCHI₂, R^(2CF)-substituted or unsubstituted alkyl,R^(2CF)-substituted or unsubstituted heteroalkyl, R^(2CF)-substituted orunsubstituted cycloalkyl, R^(2CF)-substituted or unsubstitutedheterocycloalkyl, R^(2CF)-substituted or unsubstituted aryl, orR^(2CF)-substituted or unsubstituted heteroaryl. In embodiments, R^(2C)is independently hydrogen, halogen, —CF₃, —CCl₃, —CBr₃, —CI₃, —CN, —OH,—NH₂, —COOH, —CONH₂, —NO₂, —SH, —SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂, —ONH₂,—NHC(O)NHNH₂, —NHC(O)NH₂, —NHSO₂H, —NHC(O)H, —NHC(O)OH, —NHOH, —OCF₃,—OCCl₃, —OCBr₃, —OCI₃, —OCHF₂, —OCHCl₂, —OCHBr₂, —OCHI₂,R^(2CF)-substituted or unsubstituted C₁-C₆ alkyl, R^(2CF)-substituted orunsubstituted 2 to 6 membered heteroalkyl, R^(2CF)-substituted orunsubstituted C₃-C₆ cycloalkyl, R^(2CF)-substituted or unsubstituted 3to 6 membered heterocycloalkyl, R^(2CF)-substituted or unsubstitutedphenyl, or R^(2CF)-substituted or unsubstituted 5 to 6 memberedheteroaryl. R^(2B) and R^(2C) bonded to the same nitrogen atom mayoptionally be joined to form a R^(2CF)-substituted or unsubstituted 3 to6 membered heterocycloalkyl or R^(2CF)-substituted or unsubstituted 5 to6 membered heteroaryl.

In embodiments, R^(2D) is independently hydrogen, halogen, —CF₃, —CCl₃,—CBr₃, —CI₃, —CN, —OH, —NH₂, —COOH, —CONH₂, —NO₂, —SH, —SO₃H, —SO₄H,—SO₂NH₂, —NHNH₂, —ONH₂, —NHC(O)NHNH₂, —NHC(O)NH₂, —NHSO₂H, —NHC(O)H,—NHC(O)OH, —NHOH, —OCF₃, —OCCl₃, —OCBr₃, —OCI₃, —OCHF₂, —OCHCl₂,—OCHBr₂, —OCHI₂, R^(2DF)-substituted or unsubstituted alkyl,R^(2DF)-substituted or unsubstituted heteroalkyl, R^(2DF)-substituted orunsubstituted cycloalkyl, R^(2DF)-substituted or unsubstitutedheterocycloalkyl, R^(2DF)-substituted or unsubstituted aryl, orR^(2DF)-substituted or unsubstituted heteroaryl. In embodiments, R^(2D)is independently hydrogen, halogen, —CF₃, —CCl₃, —CBr₃, —CI₃, —CN, —OH,—NH₂, —COOH, —CONH₂, —NO₂, —SH, —SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂, —ONH₂,—NHC(O)NHNH₂, —NHC(O)NH₂, —NHSO₂H, —NHC(O)H, —NHC(O)OH, —NHOH, —OCF₃,—OCCl₃, —OCBr₃, —OCI₃, —OCHF₂, —OCHCl₂, —OCHBr₂, —OCHI₂,R^(2DF)-substituted or unsubstituted C₁-C₆ alkyl, R^(2DF-)substituted orunsubstituted 2 to 6 membered heteroalkyl, R^(2DF)-substituted orunsubstituted C₃-C₆ cycloalkyl, R^(2DF)-substituted or unsubstituted 3to 6 membered heterocycloalkyl, R^(2DF)-substituted or unsubstitutedphenyl, or R^(2DF)-substituted or unsubstituted 5 to 6 memberedheteroaryl.

In embodiments, R^(3A) is independently hydrogen, halogen, —CF₃, —CCl₃,—CBr₃, —CI₃, —CN, —OH, —NH₂, —COOH, —CONH₂, —NO₂, —SH, —SO₃H, —SO₄H,—SO₂NH₂, —NHNH₂, —ONH₂, —NHC(O)NHNH₂, —NHC(O)NH₂, —NHSO₂H, —NHC(O)H,—NHC(O)OH, —NHOH, —OCF₃, —OCCl₃, —OCBr₃, —OCI₃, —OCHF₂, —OCHCl₂,—OCHBr₂, —OCHI₂, R^(3AF)-substituted or unsubstituted alkyl,R^(3AF)-substituted or unsubstituted heteroalkyl, R^(3AF)-substituted orunsubstituted cycloalkyl, R^(3AF)-substituted or unsubstitutedheterocycloalkyl, R^(3AF)-substituted or unsubstituted aryl, orR^(3AF)-substituted or unsubstituted heteroaryl. In embodiments, R^(3A)is independently hydrogen, halogen, —CF₃, —CCl₃, —CBr₃, —CI₃, —CN, —OH,—NH₂, —COOH, —CONH₂, —NO₂, —SH, —SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂, —ONH₂,—NHC(O)NHNH₂, —NHC(O)NH₂, —NHSO₂H, —NHC(O)H, —NHC(O)OH, —NHOH, —OCF₃,—OCCl₃, —OCBr₃, —OCI₃, —OCHF₂, —OCHCl₂, —OCHBr₂, —OCHI₂,R^(3AF)-substituted or unsubstituted C₁-C₆ alkyl, R^(3AF)-substituted orunsubstituted 2 to 6 membered heteroalkyl, R^(3AF)-substituted orunsubstituted C₃-C₆ cycloalkyl, R^(3AF)-substituted or unsubstituted 3to 6 membered heterocycloalkyl, R^(3AF)-substituted or unsubstitutedphenyl, or R^(3AF)-substituted or unsubstituted 5 to 6 memberedheteroaryl.

In embodiments, R^(3B) is independently hydrogen, halogen, —CF₃, —CCl₃,—CBr₃, —CI₃, —CN, —OH, —NH₂, —COOH, —CONH₂, —NO₂, —SH, —SO₃H, —SO₄H,—SO₂NH₂, —NHNH₂, —ONH₂, —NHC(O)NHNH₂, —NHC(O)NH₂, —NHSO₂H, —NHC(O)H,—NHC(O)OH, —NHOH, —OCF₃, —OCCl₃, —OCBr₃, —OCI₃, —OCHF₂, —OCHCl₂,—OCHBr₂, —OCHI₂, R^(3BF)-substituted or unsubstituted alkyl,R^(3BF)-substituted or unsubstituted heteroalkyl, R^(3BF)-substituted orunsubstituted cycloalkyl, R^(3BF)-substituted or unsubstitutedheterocycloalkyl, R^(3BF)-substituted or unsubstituted aryl, orR^(3BF)-substituted or unsubstituted heteroaryl. In embodiments, R^(3B)is independently hydrogen, halogen, —CF₃, —CCl₃, —CBr₃, —CI₃, —CN, —OH,—NH₂, —COOH, —CONH₂, —NO₂, —SH, —SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂, —ONH₂,—NHC(O)NHNH₂, —NHC(O)NH₂, —NHSO₂H, —NHC(O)H, —NHC(O)OH, —NHOH, —OCF₃,—OCCl₃, —OCBr₃, —OCI₃, —OCHF₂, —OCHCl₂, —OCHBr₂, —OCHI₂,R^(3BF)-substituted or unsubstituted C₁-C₆ alkyl, R^(3BF)-substituted orunsubstituted 2 to 6 membered heteroalkyl, R^(3BF)-substituted orunsubstituted C₃-C₆ cycloalkyl, R^(3BF)-substituted or unsubstituted 3to 6 membered heterocycloalkyl, R^(3BF)-substituted or unsubstitutedphenyl, or R^(3BF)-substituted or unsubstituted 5 to 6 memberedheteroaryl.

In embodiments, R^(3c) is independently hydrogen, halogen, —CF₃, —CCl₃,—CBr₃, —CI₃, —CN, —OH, —NH₂, —COOH, —CONH₂, —NO₂, —SH, —SO₃H, —SO₄H,—SO₂NH₂, —NHNH₂, —ONH₂, —NHC(O)NHNH₂, —NHC(O)NH₂, —NHSO₂H, —NHC(O)H,—NHC(O)OH, —NHOH, —OCF₃, —OCCl₃, —OCBr₃, —OCI₃, —OCHF₂, —OCHCl₂,—OCHBr₂, —OCHI₂, R^(3CF)-substituted or unsubstituted alkyl,R^(3CF)-substituted or unsubstituted heteroalkyl, R^(3CF)-substituted orunsubstituted cycloalkyl, R^(3CF)-substituted or unsubstitutedheterocycloalkyl, R^(3CF)-substituted or unsubstituted aryl, orR^(3CF)-substituted or unsubstituted heteroaryl. In embodiments, R^(3C)is independently hydrogen, halogen, —CF₃, —CCl₃, —CBr₃, —CI₃, —CN, —OH,—NH₂, —COOH, —CONH₂, —NO₂, —SH, —SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂, —ONH₂,—NHC(O)NHNH₂, —NHC(O)NH₂, —NHSO₂H, —NHC(O)H, —NHC(O)OH, —NHOH, —OCF₃,—OCCl₃, —OCBr₃, —OCI₃, —OCHF₂, —OCHCl₂, —OCHBr₂, —OCHI₂,R^(3CF)-substituted or unsubstituted C₁-C₆ alkyl, R^(3CF)-substituted orunsubstituted 2 to 6 membered heteroalkyl, R^(3CF)-substituted orunsubstituted C₃-C₆ cycloalkyl, R^(3CF)-substituted or unsubstituted 3to 6 membered heterocycloalkyl, R^(3CF)-substituted or unsubstitutedphenyl, or R^(3CF)-substituted or unsubstituted 5 to 6 memberedheteroaryl. R^(3B) and R^(3c) bonded to the same nitrogen atom mayoptionally be joined to form a R^(3CF)-substituted or unsubstituted 3 to6 membered heterocycloalkyl or R^(3CF)-substituted or unsubstituted 5 to6 membered heteroaryl.

In embodiments, R^(3D) is independently hydrogen, halogen, —CF₃, —CCl₃,—CBr₃, —CI₃, —CN, —OH, —NH₂, —COOH, —CONH₂, —NO₂, —SH, —SO₃H, —SO₄H,—SO₂NH₂, —NHNH₂, —ONH₂, —NHC(O)NHNH₂, —NHC(O)NH₂, —NHSO₂H, —NHC(O)H,—NHC(O)OH, —NHOH, —OCF₃, —OCCl₃, —OCBr₃, —OCI₃, —OCHF₂, —OCHCl₂,—OCHBr₂, —OCHI₂, R^(3DF)-substituted or unsubstituted alkyl,R^(3DF)-substituted or unsubstituted heteroalkyl, R^(3DF)-substituted orunsubstituted cycloalkyl, R^(3DF)-substituted or unsubstitutedheterocycloalkyl, R^(3DF)-substituted or unsubstituted aryl, orR^(3DF)-substituted or unsubstituted heteroaryl. In embodiments, R^(3D)is independently hydrogen, halogen, —CF₃, —CCl₃, —CBr₃, —CI₃, —CN, —OH,—NH₂, —COOH, —CONH₂, —NO₂, —SH, —SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂, —ONH₂,—NHC(O)NHNH₂, —NHC(O)NH₂, —NHSO₂H, —NHC(O)H, —NHC(O)OH, —NHOH, —OCF₃,—OCCl₃, —OCBr₃, —OCI₃, —OCHF₂, —OCHCl₂, —OCHBr₂, —OCHI₂,R^(3DF)-substituted or unsubstituted C₁-C₆ alkyl, R^(3DF-)substituted orunsubstituted 2 to 6 membered heteroalkyl, R^(3DF)-substituted orunsubstituted C₃-C₆ cycloalkyl, R^(3DF)-substituted or unsubstituted 3to 6 membered heterocycloalkyl, R^(3DF)-substituted or unsubstitutedphenyl, or R^(3DF)-substituted or unsubstituted 5 to 6 memberedheteroaryl.

In embodiments, R^(4A) is independently hydrogen, halogen, —CF₃, —CCl₃,—CBr₃, —CI₃, —CN, —OH, —NH₂, —COOH, —CONH₂, —NO₂, —SH, —SO₃H, —SO₄H,—SO₂NH₂, —NHNH₂, —ONH₂, —NHC(O)NHNH₂, —NHC(O)NH₂, —NHSO₂H, —NHC(O)H,—NHC(O)OH, —NHOH, —OCF₃, —OCCl₃, —OCBr₃, —OCI₃, —OCHF₂, —OCHCl₂,—OCHBr₂, —OCHI₂, R^(4AF)-substituted or unsubstituted alkyl,R^(4AF)-substituted or unsubstituted heteroalkyl, R^(4AF)-substituted orunsubstituted cycloalkyl, R^(4AF)-substituted or unsubstitutedheterocycloalkyl, R^(4AF)-substituted or unsubstituted aryl, orR^(4AF)-substituted or unsubstituted heteroaryl. In embodiments, R^(4A)is independently hydrogen, halogen, —CF₃, —CCl₃, —CBr₃, —CI₃, —CN, —OH,—NH₂, —COOH, —CONH₂, —NO₂, —SH, —SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂, —ONH₂,—NHC(O)NHNH₂, —NHC(O)NH₂, —NHSO₂H, —NHC(O)H, —NHC(O)OH, —NHOH, —OCF₃,—OCCl₃, —OCBr₃, —OCI₃, —OCHF₂, —OCHCl₂, —OCHBr₂, —OCHI₂,R^(4AF)-substituted or unsubstituted C₁-C₆ alkyl, R^(4A)-substituted orunsubstituted 2 to 6 membered heteroalkyl, R^(4AF)-substituted orunsubstituted C₃-C₆ cycloalkyl, R^(4AF)-substituted or unsubstituted 3to 6 membered heterocycloalkyl, R^(4AF)-substituted or unsubstitutedphenyl, or R^(4AF)-substituted or unsubstituted 5 to 6 memberedheteroaryl.

In embodiments, R^(4B) is independently hydrogen, halogen, —CF₃, —CCl₃,—CBr₃, —CI₃, —CN, —OH, —NH₂, —COOH, —CONH₂, —NO₂, —SH, —SO₃H, —SO₄H,—SO₂NH₂, —NHNH₂, —ONH₂, —NHC(O)NHNH₂, —NHC(O)NH₂, —NHSO₂H, —NHC(O)H,—NHC(O)OH, —NHOH, —OCF₃, —OCCl₃, —OCBr₃, —OCI₃, —OCHF₂, —OCHCl₂,—OCHBr₂, —OCHI₂, R^(4BF)-substituted or unsubstituted alkyl,R^(4BF)-substituted or unsubstituted heteroalkyl, R^(4BF)-substituted orunsubstituted cycloalkyl, R^(4BF)-substituted or unsubstitutedheterocycloalkyl, R^(4BF)-substituted or unsubstituted aryl, orR^(4BF)-substituted or unsubstituted heteroaryl. In embodiments, R^(4B)is independently hydrogen, halogen, —CF₃, —CCl₃, —CBr₃, —CI₃, —CN, —OH,—NH₂, —COOH, —CONH₂, —NO₂, —SH, —SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂, —ONH₂,—NHC(O)NHNH₂, —NHC(O)NH₂, —NHSO₂H, —NHC(O)H, —NHC(O)OH, —NHOH, —OCF₃,—OCCl₃, —OCBr₃, —OCI₃, —OCHF₂, —OCHCl₂, —OCHBr₂, —OCHI₂,R^(4BF)-substituted or unsubstituted C₁-C₆ alkyl, R^(4BF-)substituted orunsubstituted 2 to 6 membered heteroalkyl, R^(4BF)-substituted orunsubstituted C₃-C₆ cycloalkyl, R^(4BF)-substituted or unsubstituted 3to 6 membered heterocycloalkyl, R^(4BF)-substituted or unsubstitutedphenyl, or R^(4BF)-substituted or unsubstituted 5 to 6 memberedheteroaryl.

In embodiments, R^(4C) is independently hydrogen, halogen, —CF₃, —CCl₃,—CBr₃, —CI₃, —CN, —OH, —NH₂, —COOH, —CONH₂, —NO₂, —SH, —SO₃H, —SO₄H,—SO₂NH₂, —NHNH₂, —ONH₂, —NHC(O)NHNH₂, —NHC(O)NH₂, —NHSO₂H, —NHC(O)H,—NHC(O)OH, —NHOH, —OCF₃, —OCCl₃, —OCBr₃, —OCI₃, —OCHF₂, —OCHCl₂,—OCHBr₂, —OCHI₂, R^(4CF)-substituted or unsubstituted alkyl,R^(4C)-substituted or unsubstituted heteroalkyl, R^(4C)-substituted orunsubstituted cycloalkyl, R^(4CF)-substituted or unsubstitutedheterocycloalkyl, R^(4CF)-substituted or unsubstituted aryl, orR^(4CF)-substituted or unsubstituted heteroaryl. In embodiments, R^(4C)is independently hydrogen, halogen, —CF₃, —CCl₃, —CBr₃, —CI₃, —CN, —OH,—NH₂, —COOH, —CONH₂, —NO₂, —SH, —SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂, —ONH₂,—NHC(O)NHNH₂, —NHC(O)NH₂, —NHSO₂H, —NHC(O)H, —NHC(O)OH, —NHOH, —OCF₃,—OCCl₃, —OCBr₃, —OCI₃, —OCHF₂, —OCHCl₂, —OCHBr₂, —OCHI₂,R^(4CF)-substituted or unsubstituted C₁-C₆ alkyl, R^(4CF)-substituted orunsubstituted 2 to 6 membered heteroalkyl, R^(4CF)-substituted orunsubstituted C₃-C₆ cycloalkyl, R^(4CF)-substituted or unsubstituted 3to 6 membered heterocycloalkyl, R^(4CF)-substituted or unsubstitutedphenyl, or R^(4CF)-substituted or unsubstituted 5 to 6 memberedheteroaryl. R^(4B) and R^(4c) bonded to the same nitrogen atom mayoptionally be joined to form a R^(4CF)-substituted or unsubstituted 3 to6 membered heterocycloalkyl or R^(4CF)-substituted or unsubstituted 5 to6 membered heteroaryl.

In embodiments, R^(4D) is independently hydrogen, halogen, —CF₃, —CCl₃,—CBr₃, —CI₃, —CN, —OH, —NH₂, —COOH, —CONH₂, —NO₂, —SH, —SO₃H, —SO₄H,—SO₂NH₂, —NHNH₂, —ONH₂, —NHC(O)NHNH₂, —NHC(O)NH₂, —NHSO₂H, —NHC(O)H,—NHC(O)OH, —NHOH, —OCF₃, —OCCl₃, —OCBr₃, —OCI₃, —OCHF₂, —OCHCl₂,—OCHBr₂, —OCHI₂, R^(4DF)-substituted or unsubstituted alkyl,R^(4DF)-substituted or unsubstituted heteroalkyl, R^(4DF)-substituted orunsubstituted cycloalkyl, R^(4DF)-substituted or unsubstitutedheterocycloalkyl, R^(4DF)-substituted or unsubstituted aryl, orR^(4DF)-substituted or unsubstituted heteroaryl. In embodiments, R^(4D)is independently hydrogen, halogen, —CF₃, —CCl₃, —CBr₃, —CI₃, —CN, —OH,—NH₂, —COOH, —CONH₂, —NO₂, —SH, —SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂, —ONH₂,—NHC(O)NHNH₂, —NHC(O)NH₂, —NHSO₂H, —NHC(O)H, —NHC(O)OH, —NHOH, —OCF₃,—OCCl₃, —OCBr₃, —OCI₃, —OCHF₂, —OCHCl₂, —OCHBr₂, —OCHI₂,R^(4DF)-substituted or unsubstituted C₁-C₆ alkyl, R^(4DF)-substituted orunsubstituted 2 to 6 membered heteroalkyl, R^(4DF)-substituted orunsubstituted C₃-C₆ cycloalkyl, R^(4DF)-substituted or unsubstituted 3to 6 membered heterocycloalkyl, R^(4DF)-substituted or unsubstitutedphenyl, or R^(4DF)-substituted or unsubstituted 5 to 6 memberedheteroaryl.

In embodiments, R^(5A) is independently hydrogen, halogen, —CF₃, —CCl₃,—CBr₃, —CI₃, —CN, —OH, —NH₂, —COOH, —CONH₂, —NO₂, —SH, —SO₃H, —SO₄H,—SO₂NH₂, —NHNH₂, —ONH₂, —NHC(O)NHNH₂, —NHC(O)NH₂, —NHSO₂H, —NHC(O)H,—NHC(O)OH, —NHOH, —OCF₃, —OCCl₃, —OCBr₃, —OCI₃, —OCHF₂, —OCHCl₂,—OCHBr₂, —OCHI₂, R^(5AF)-substituted or unsubstituted alkyl,R^(5AF)-substituted or unsubstituted heteroalkyl, R^(5AF)-substituted orunsubstituted cycloalkyl, R^(5AF)-substituted or unsubstitutedheterocycloalkyl, R^(5AF)-substituted or unsubstituted aryl, orR^(5AF)-substituted or unsubstituted heteroaryl. In embodiments, R^(5AF)is independently hydrogen, halogen, —CF₃, —CCl₃, —CBr₃, —CI₃, —CN, —OH,—NH₂, —COOH, —CONH₂, —NO₂, —SH, —SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂, —ONH₂,—NHC(O)NHNH₂, —NHC(O)NH₂, —NHSO₂H, —NHC(O)H, —NHC(O)OH, —NHOH, —OCF₃,—OCCl₃, —OCBr₃, —OCI₃, —OCHF₂, —OCHCl₂, —OCHBr₂, —OCHI₂,R^(5AF)-substituted or unsubstituted C₁-C₆ alkyl, R^(5AF)-substituted orunsubstituted 2 to 6 membered heteroalkyl, R^(5AF)-substituted orunsubstituted C₃-C₆ cycloalkyl, R^(5AF)-substituted or unsubstituted 3to 6 membered heterocycloalkyl, R^(5AF)-substituted or unsubstitutedphenyl, or R^(5AF)-substituted or unsubstituted 5 to 6 memberedheteroaryl.

In embodiments, R^(5B) is independently hydrogen, halogen, —CF₃, —CCl₃,—CBr₃, —CI₃, —CN, —OH, —NH₂, —COOH, —CONH₂, —NO₂, —SH, —SO₃H, —SO₄H,—SO₂NH₂, —NHNH₂, —ONH₂, —NHC(O)NHNH₂, —NHC(O)NH₂, —NHSO₂H, —NHC(O)H,—NHC(O)OH, —NHOH, —OCF₃, —OCCl₃, —OCBr₃, —OCI₃, —OCHF₂, —OCHCl₂,—OCHBr₂, —OCHI₂, R^(5BF)-substituted or unsubstituted alkyl,R^(5BF)-substituted or unsubstituted heteroalkyl, R^(5BF)-substituted orunsubstituted cycloalkyl, R^(5BF)-substituted or unsubstitutedheterocycloalkyl, R^(5BF)-substituted or unsubstituted aryl, orR^(5BF)-substituted or unsubstituted heteroaryl. In embodiments, R^(5BF)is independently hydrogen, halogen, —CF₃, —CCl₃, —CBr₃, —CI₃, —CN, —OH,—NH₂, —COOH, —CONH₂, —NO₂, —SH, —SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂, —ONH₂,—NHC(O)NHNH₂, —NHC(O)NH₂, —NHSO₂H, —NHC(O)H, —NHC(O)OH, —NHOH, —OCF₃,—OCCl₃, —OCBr₃, —OCI₃, —OCHF₂, —OCHCl₂, —OCHBr₂, —OCHI₂,R^(5BF)-substituted or unsubstituted C₁-C₆ alkyl, R^(5BF)-substituted orunsubstituted 2 to 6 membered heteroalkyl, R^(5BF)-substituted orunsubstituted C₃-C₆ cycloalkyl, R^(5BF)-substituted or unsubstituted 3to 6 membered heterocycloalkyl, R^(5BF)-substituted or unsubstitutedphenyl, or R^(5BF)-substituted or unsubstituted 5 to 6 memberedheteroaryl.

In embodiments, R^(5C) is independently hydrogen, halogen, —CF₃, —CCl₃,—CBr₃, —CI₃, —CN, —OH, —NH₂, —COOH, —CONH₂, —NO₂, —SH, —SO₃H, —SO₄H,—SO₂NH₂, —NHNH₂, —ONH₂, —NHC(O)NHNH₂, —NHC(O)NH₂, —NHSO₂H, —NHC(O)H,—NHC(O)OH, —NHOH, —OCF₃, —OCCl₃, —OCBr₃, —OCI₃, —OCHF₂, —OCHCl₂,—OCHBr₂, —OCHI₂, R^(5CF)-substituted or unsubstituted alkyl,R^(5CF)-substituted or unsubstituted heteroalkyl, R^(5CF)-substituted orunsubstituted cycloalkyl, R^(5CF)-substituted or unsubstitutedheterocycloalkyl, R^(5CF)-substituted or unsubstituted aryl, orR^(5CF)-substituted or unsubstituted heteroaryl. In embodiments, R^(5C)is independently hydrogen, halogen, —CF₃, —CCl₃, —CBr₃, —CI₃, —CN, —OH,—NH₂, —COOH, —CONH₂, —NO₂, —SH, —SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂, —ONH₂,—NHC(O)NHNH₂, —NHC(O)NH₂, —NHSO₂H, —NHC(O)H, —NHC(O)OH, —NHOH, —OCF₃,—OCCl₃, —OCBr₃, —OCI₃, —OCHF₂, —OCHCl₂, —OCHBr₂, —OCHI₂,R^(5CF)-substituted or unsubstituted C₁-C₆ alkyl, R^(5CF)-substituted orunsubstituted 2 to 6 membered heteroalkyl, R^(5C)-substituted orunsubstituted C₃-C₆ cycloalkyl, R^(5C)-substituted or unsubstituted 3 to6 membered heterocycloalkyl, R^(5C)-substituted or unsubstituted phenyl,or R^(5CF)-substituted or unsubstituted 5 to 6 membered heteroaryl.R^(5B) and R^(5C) bonded to the same nitrogen atom may optionally bejoined to form a R^(5CF)-substituted or unsubstituted 3 to 6 memberedheterocycloalkyl or R^(5C)-substituted or unsubstituted 5 to 6 memberedheteroaryl.

In embodiments, R^(5D) is independently hydrogen, halogen, —CF₃, —CCl₃,—CBr₃, —CI₃, —CN, —OH, —NH₂, —COOH, —CONH₂, —NO₂, —SH, —SO₃H, —SO₄H,—SO₂NH₂, —NHNH₂, —ONH₂, —NHC(O)NHNH₂, —NHC(O)NH₂, —NHSO₂H, —NHC(O)H,—NHC(O)OH, —NHOH, —OCF₃, —OCCl₃, —OCBr₃, —OCI₃, —OCHF₂, —OCHCl₂,—OCHBr₂, —OCHI₂, R^(5DF)-substituted or unsubstituted alkyl,R^(5DF)-substituted or unsubstituted heteroalkyl, R^(5DF)-substituted orunsubstituted cycloalkyl, R^(5DF)-substituted or unsubstitutedheterocycloalkyl, R^(5DF)-substituted or unsubstituted aryl, orR^(5DF)-substituted or unsubstituted heteroaryl. In embodiments, R^(5D)is independently hydrogen, halogen, —CF₃, —CCl₃, —CBr₃, —CI₃, —CN, —OH,—NH₂, —COOH, —CONH₂, —NO₂, —SH, —SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂, —ONH₂,—NHC(O)NHNH₂, —NHC(O)NH₂, —NHSO₂H, —NHC(O)H, —NHC(O)OH, —NHOH, —OCF₃,—OCCl₃, —OCBr₃, —OCI₃, —OCHF₂, —OCHCl₂, —OCHBr₂, —OCHI₂,R^(5DF)-substituted or unsubstituted C₁-C₆ alkyl, R^(5DF)-substituted orunsubstituted 2 to 6 membered heteroalkyl, R^(5DF)-substituted orunsubstituted C₃-C₆ cycloalkyl, R^(5DF)-substituted or unsubstituted 3to 6 membered heterocycloalkyl, R^(5DF)-substituted or unsubstitutedphenyl, or R^(5D)-substituted or unsubstituted 5 to 6 memberedheteroaryl.

In embodiments, R^(6A) is independently hydrogen, halogen, —CF₃, —CCl₃,—CBr₃, —CI₃, —CN, —OH, —NH₂, —COOH, —CONH₂, —NO₂, —SH, —SO₃H, —SO₄H,—SO₂NH₂, —NHNH₂, —ONH₂, —NHC(O)NHNH₂, —NHC(O)NH₂, —NHSO₂H, —NHC(O)H,—NHC(O)OH, —NHOH, —OCF₃, —OCCl₃, —OCBr₃, —OCI₃, —OCHF₂, —OCHCl₂,—OCHBr₂, —OCHI₂, R^(6AF)-substituted or unsubstituted alkyl,R^(6AF)-substituted or unsubstituted heteroalkyl, R^(6AF)-substituted orunsubstituted cycloalkyl, R^(6AF)-substituted or unsubstitutedheterocycloalkyl, R^(6AF)-substituted or unsubstituted aryl, orR^(6AF)-substituted or unsubstituted heteroaryl. In embodiments, R^(6A)is independently hydrogen, halogen, —CF₃, —CCl₃, —CBr₃, —CI₃, —CN, —OH,—NH₂, —COOH, —CONH₂, —NO₂, —SH, —SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂, —ONH₂,—NHC(O)NHNH₂, —NHC(O)NH₂, —NHSO₂H, —NHC(O)H, —NHC(O)OH, —NHOH, —OCF₃,—OCCl₃, —OCBr₃, —OCI₃, —OCHF₂, —OCHCl₂, —OCHBr₂, —OCHI₂,R^(6AF)-substituted or unsubstituted C₁-C₆ alkyl, R^(6AF)-substituted orunsubstituted 2 to 6 membered heteroalkyl, R^(6AF)-substituted orunsubstituted C₃-C₆ cycloalkyl, R^(6AF)-substituted or unsubstituted 3to 6 membered heterocycloalkyl, R^(6AF)-substituted or unsubstitutedphenyl, or R^(6AF)-substituted or unsubstituted 5 to 6 memberedheteroaryl.

In embodiments, R^(6B) is independently hydrogen, halogen, —CF₃, —CCl₃,—CBr₃, —CI₃, —CN, —OH, —NH₂, —COOH, —CONH₂, —NO₂, —SH, —SO₃H, —SO₄H,—SO₂NH₂, —NHNH₂, —ONH₂, —NHC(O)NHNH₂, —NHC(O)NH₂, —NHSO₂H, —NHC(O)H,—NHC(O)OH, —NHOH, —OCF₃, —OCCl₃, —OCBr₃, —OCI₃, —OCHF₂, —OCHCl₂,—OCHBr₂, —OCHI₂, R^(6BF)-substituted or unsubstituted alkyl,R^(6BF)-substituted or unsubstituted heteroalkyl, R^(6BF)-substituted orunsubstituted cycloalkyl, R^(6BF)-substituted or unsubstitutedheterocycloalkyl, R^(6BF)-substituted or unsubstituted aryl, orR^(6BF)-substituted or unsubstituted heteroaryl. In embodiments, R^(6B)is independently hydrogen, halogen, —CF₃, —CCl₃, —CBr₃, —CI₃, —CN, —OH,—NH₂, —COOH, —CONH₂, —NO₂, —SH, —SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂, —ONH₂,—NHC(O)NHNH₂, —NHC(O)NH₂, —NHSO₂H, —NHC(O)H, —NHC(O)OH, —NHOH, —OCF₃,—OCCl₃, —OCBr₃, —OCI₃, —OCHF₂, —OCHCl₂, —OCHBr₂, —OCHI₂,R^(6BF)-substituted or unsubstituted C₁-C₆ alkyl, R^(6BF-)substituted orunsubstituted 2 to 6 membered heteroalkyl, R^(6BF)-substituted orunsubstituted C₃-C₆ cycloalkyl, R^(6BF)-substituted or unsubstituted 3to 6 membered heterocycloalkyl, R^(6BF)-substituted or unsubstitutedphenyl, or R^(6BF)-substituted or unsubstituted 5 to 6 memberedheteroaryl.

In embodiments, R^(6C) is independently hydrogen, halogen, —CF₃, —CCl₃,—CBr₃, —CI₃, —CN, —OH, —NH₂, —COOH, —CONH₂, —NO₂, —SH, —SO₃H, —SO₄H,—SO₂NH₂, —NHNH₂, —ONH₂, —NHC(O)NHNH₂, —NHC(O)NH₂, —NHSO₂H, —NHC(O)H,—NHC(O)OH, —NHOH, —OCF₃, —OCCl₃, —OCBr₃, —OCI₃, —OCHF₂, —OCHCl₂,—OCHBr₂, —OCHI₂, R^(6CF)-substituted or unsubstituted alkyl,R^(6CF)-substituted or unsubstituted heteroalkyl, R^(6CF)-substituted orunsubstituted cycloalkyl, R^(6CF)-substituted or unsubstitutedheterocycloalkyl, R^(6CF)-substituted or unsubstituted aryl, orR^(6CF)-substituted or unsubstituted heteroaryl. In embodiments, R^(6C)is independently hydrogen, halogen, —CF₃, —CCl₃, —CBr₃, —CI₃, —CN, —OH,—NH₂, —COOH, —CONH₂, —NO₂, —SH, —SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂, —ONH₂,—NHC(O)NHNH₂, —NHC(O)NH₂, —NHSO₂H, —NHC(O)H, —NHC(O)OH, —NHOH, —OCF₃,—OCCl₃, —OCBr₃, —OCI₃, —OCHF₂, —OCHCl₂, —OCHBr₂, —OCHI₂,R^(6CF)-substituted or unsubstituted C₁-C₆ alkyl, R^(6CF)-substituted orunsubstituted 2 to 6 membered heteroalkyl, R^(6CF)-substituted orunsubstituted C₃-C₆ cycloalkyl, R^(6CF)-substituted or unsubstituted 3to 6 membered heterocycloalkyl, R^(6CF)-substituted or unsubstitutedphenyl, or R^(6CF)-substituted or unsubstituted 5 to 6 memberedheteroaryl. R^(6B) and R^(6C) bonded to the same nitrogen atom mayoptionally be joined to form a R^(6CF)-substituted or unsubstituted 3 to6 membered heterocycloalkyl or R^(6CF)-substituted or unsubstituted 5 to6 membered heteroaryl.

In embodiments, R^(6D) is independently hydrogen, halogen, —CF₃, —CCl₃,—CBr₃, —CI₃, —CN, —OH, —NH₂, —COOH, —CONH₂, —NO₂, —SH, —SO₃H, —SO₄H,—SO₂NH₂, —NHNH₂, —ONH₂, —NHC(O)NHNH₂, —NHC(O)NH₂, —NHSO₂H, —NHC(O)H,—NHC(O)OH, —NHOH, —OCF₃, —OCCl₃, —OCBr₃, —OCI₃, —OCHF₂, —OCHCl₂,—OCHBr₂, —OCHI₂, R^(6DF)-substituted or unsubstituted alkyl,R^(6DF)-substituted or unsubstituted heteroalkyl, R^(6DF)-substituted orunsubstituted cycloalkyl, R^(6DF)-substituted or unsubstitutedheterocycloalkyl, R^(6DF)-substituted or unsubstituted aryl, orR^(6DF)-substituted or unsubstituted heteroaryl. In embodiments, R^(6D)is independently hydrogen, halogen, —CF₃, —CCl₃, —CBr₃, —CI₃, —CN, —OH,—NH₂, —COOH, —CONH₂, —NO₂, —SH, —SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂, —ONH₂,—NHC(O)NHNH₂, —NHC(O)NH₂, —NHSO₂H, —NHC(O)H, —NHC(O)OH, —NHOH, —OCF₃,—OCCl₃, —OCBr₃, —OCI₃, —OCHF₂, —OCHCl₂, —OCHBr₂, —OCHI₂,R^(6DF)-substituted or unsubstituted C₁-C₆ alkyl, R^(6DF)-substituted orunsubstituted 2 to 6 membered heteroalkyl, R^(6DF)-substituted orunsubstituted C₃-C₆ cycloalkyl, R^(6DF)-substituted or unsubstituted 3to 6 membered heterocycloalkyl, R^(6DF)-substituted or unsubstitutedphenyl, or R^(6DF)-substituted or unsubstituted 5 to 6 memberedheteroaryl.

In embodiments, R^(7A) is independently hydrogen, halogen, —CF₃, —CCl₃,—CBr₃, —CI₃, —CN, —OH, —NH₂, —COOH, —CONH₂, —NO₂, —SH, —SO₃H, —SO₄H,—SO₂NH₂, —NHNH₂, —ONH₂, —NHC(O)NHNH₂, —NHC(O)NH₂, —NHSO₂H, —NHC(O)H,—NHC(O)OH, —NHOH, —OCF₃, —OCCl₃, —OCBr₃, —OCI₃, —OCHF₂, —OCHCl₂,—OCHBr₂, —OCHI₂, R^(7AF)-substituted or unsubstituted alkyl,R^(7AF)-substituted or unsubstituted heteroalkyl, R^(7AF)-substituted orunsubstituted cycloalkyl, R^(7AF)-substituted or unsubstitutedheterocycloalkyl, R^(7AF)-substituted or unsubstituted aryl, orR^(7AF)-substituted or unsubstituted heteroaryl. In embodiments, R^(7A)is independently hydrogen, halogen, —CF₃, —CCl₃, —CBr₃, —CI₃, —CN, —OH,—NH₂, —COOH, —CONH₂, —NO₂, —SH, —SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂, —ONH₂,—NHC(O)NHNH₂, —NHC(O)NH₂, —NHSO₂H, —NHC(O)H, —NHC(O)OH, —NHOH, —OCF₃,—OCCl₃, —OCBr₃, —OCI₃, —OCHF₂, —OCHCl₂, —OCHBr₂, —OCHI₂,R^(7AF)-substituted or unsubstituted C₁-C₆ alkyl, R^(7A)-substituted orunsubstituted 2 to 6 membered heteroalkyl, R^(7AF)-substituted orunsubstituted C₃-C₆ cycloalkyl, R^(7AF)-substituted or unsubstituted 3to 6 membered heterocycloalkyl, R^(7AF)-substituted or unsubstitutedphenyl, or R^(7AF)-substituted or unsubstituted 5 to 6 memberedheteroaryl.

In embodiments, R^(7B) is independently hydrogen, halogen, —CF₃, —CCl₃,—CBr₃, —CI₃, —CN, —OH, —NH₂, —COOH, —CONH₂, —NO₂, —SH, —SO₃H, —SO₄H,—SO₂NH₂, —NHNH₂, —ONH₂, —NHC(O)NHNH₂, —NHC(O)NH₂, —NHSO₂H, —NHC(O)H,—NHC(O)OH, —NHOH, —OCF₃, —OCCl₃, —OCBr₃, —OCI₃, —OCHF₂, —OCHCl₂,—OCHBr₂, —OCHI₂, R^(7BF)-substituted or unsubstituted alkyl,R^(7BF)-substituted or unsubstituted heteroalkyl, R^(7BF)-substituted orunsubstituted cycloalkyl, R^(7BF)-substituted or unsubstitutedheterocycloalkyl, R^(7BF)-substituted or unsubstituted aryl, orR^(7BF)-substituted or unsubstituted heteroaryl. In embodiments, R^(7B)is independently hydrogen, halogen, —CF₃, —CCl₃, —CBr₃, —CI₃, —CN, —OH,—NH₂, —COOH, —CONH₂, —NO₂, —SH, —SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂, —ONH₂,—NHC(O)NHNH₂, —NHC(O)NH₂, —NHSO₂H, —NHC(O)H, —NHC(O)OH, —NHOH, —OCF₃,—OCCl₃, —OCBr₃, —OCI₃, —OCHF₂, —OCHCl₂, —OCHBr₂, —OCHI₂,R^(7BF)-substituted or unsubstituted C₁-C₆ alkyl, R^(7BF)-substituted orunsubstituted 2 to 6 membered heteroalkyl, R^(7BF)-substituted orunsubstituted C₃-C₆ cycloalkyl, R^(7BF)-substituted or unsubstituted 3to 6 membered heterocycloalkyl, R^(7BF)-substituted or unsubstitutedphenyl, or R^(7BF)-substituted or unsubstituted 5 to 6 memberedheteroaryl.

In embodiments, R^(7C) is independently hydrogen, halogen, —CF₃, —CCl₃,—CBr₃, —CI₃, —CN, —OH, —NH₂, —COOH, —CONH₂, —NO₂, —SH, —SO₃H, —SO₄H,—SO₂NH₂, —NHNH₂, —ONH₂, —NHC(O)NHNH₂, —NHC(O)NH₂, —NHSO₂H, —NHC(O)H,—NHC(O)OH, —NHOH, —OCF₃, —OCCl₃, —OCBr₃, —OCI₃, —OCHF₂, —OCHCl₂,—OCHBr₂, —OCHI₂, R^(7CF)-substituted or unsubstituted alkyl,R^(7CF)-substituted or unsubstituted heteroalkyl, R^(7CF)-substituted orunsubstituted cycloalkyl, R^(7CF)-substituted or unsubstitutedheterocycloalkyl, R^(7CF)-substituted or unsubstituted aryl, orR^(7CF)-substituted or unsubstituted heteroaryl. In embodiments, R^(7C)is independently hydrogen, halogen, —CF₃, —CCl₃, —CBr₃, —CI₃, —CN, —OH,—NH₂, —COOH, —CONH₂, —NO₂, —SH, —SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂, —ONH₂,—NHC(O)NHNH₂, —NHC(O)NH₂, —NHSO₂H, —NHC(O)H, —NHC(O)OH, —NHOH, —OCF₃,—OCCl₃, —OCBr₃, —OCI₃, —OCHF₂, —OCHCl₂, —OCHBr₂, —OCHI₂,R^(7CF)-substituted or unsubstituted C₁-C₆ alkyl, R^(7CF)-substituted orunsubstituted 2 to 6 membered heteroalkyl, R^(7CF)-substituted orunsubstituted C₃-C₆ cycloalkyl, R^(7CF)-substituted or unsubstituted 3to 6 membered heterocycloalkyl, R^(7CF)-substituted or unsubstitutedphenyl, or R^(7CF)-substituted or unsubstituted 5 to 6 memberedheteroaryl. R^(7B) and R^(7C) bonded to the same nitrogen atom mayoptionally be joined to form a R^(7CF)-substituted or unsubstituted 3 to6 membered heterocycloalkyl or R^(7CF)-substituted or unsubstituted 5 to6 membered heteroaryl.

In embodiments, R^(7D) is independently hydrogen, halogen, —CF₃, —CCl₃,—CBr₃, —CI₃, —CN, —OH, —NH₂, —COOH, —CONH₂, —NO₂, —SH, —SO₃H, —SO₄H,—SO₂NH₂, —NHNH₂, —ONH₂, —NHC(O)NHNH₂, —NHC(O)NH₂, —NHSO₂H, —NHC(O)H,—NHC(O)OH, —NHOH, —OCF₃, —OCCl₃, —OCBr₃, —OCI₃, —OCHF₂, —OCHCl₂,—OCHBr₂, —OCHI₂, R^(7DF)-substituted or unsubstituted alkyl,R^(7DF)-substituted or unsubstituted heteroalkyl, R^(7DF)-substituted orunsubstituted cycloalkyl, R^(7DF)-substituted or unsubstitutedheterocycloalkyl, R^(7DF)-substituted or unsubstituted aryl, orR^(7DF)-substituted or unsubstituted heteroaryl. In embodiments, R^(7D)is independently hydrogen, halogen, —CF₃, —CCl₃, —CBr₃, —CI₃, —CN, —OH,—NH₂, —COOH, —CONH₂, —NO₂, —SH, —SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂, —ONH₂,—NHC(O)NHNH₂, —NHC(O)NH₂, —NHSO₂H, —NHC(O)H, —NHC(O)OH, —NHOH, —OCF₃,—OCCl₃, —OCBr₃, —OCI₃, —OCHF₂, —OCHCl₂, —OCHBr₂, —OCHI₂,R^(7DF)-substituted or unsubstituted C₁-C₆ alkyl, R^(7DF)-substituted orunsubstituted 2 to 6 membered heteroalkyl, R^(7DF)-substituted orunsubstituted C₃-C₆ cycloalkyl, R^(7DF)-substituted or unsubstituted 3to 6 membered heterocycloalkyl, R^(7DF)-substituted or unsubstitutedphenyl, or R^(7DF)-substituted or unsubstituted 5 to 6 memberedheteroaryl.

In embodiments, R^(8A) is independently hydrogen, halogen, —CF₃, —CCl₃,—CBr₃, —CI₃, —CN, —OH, —NH₂, —COOH, —CONH₂, —NO₂, —SH, —SO₃H, —SO₄H,—SO₂NH₂, —NHNH₂, —ONH₂, —NHC(O)NHNH₂, —NHC(O)NH₂, —NHSO₂H, —NHC(O)H,—NHC(O)OH, —NHOH, —OCF₃, —OCCl₃, —OCBr₃, —OCI₃, —OCHF₂, —OCHCl₂,—OCHBr₂, —OCHI₂, R^(8AF)-substituted or unsubstituted alkyl,R^(8AF)-substituted or unsubstituted heteroalkyl, R^(8AF)-substituted orunsubstituted cycloalkyl, R^(8AF)-substituted or unsubstitutedheterocycloalkyl, R^(8AF)-substituted or unsubstituted aryl, orR^(8AF)-substituted or unsubstituted heteroaryl. In embodiments, R^(8A)is independently hydrogen, halogen, —CF₃, —CCl₃, —CBr₃, —CI₃, —CN, —OH,—NH₂, —COOH, —CONH₂, —NO₂, —SH, —SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂, —ONH₂,—NHC(O)NHNH₂, —NHC(O)NH₂, —NHSO₂H, —NHC(O)H, —NHC(O)OH, —NHOH, —OCF₃,—OCCl₃, —OCBr₃, —OCI₃, —OCHF₂, —OCHCl₂, —OCHBr₂, —OCHI₂,R^(8AF)-substituted or unsubstituted C₁-C₆ alkyl, R^(8A)-substituted orunsubstituted 2 to 6 membered heteroalkyl, R^(8AF)-substituted orunsubstituted C₃-C₆ cycloalkyl, R^(8AF)-substituted or unsubstituted 3to 6 membered heterocycloalkyl, R^(8AF)-substituted or unsubstitutedphenyl, or R^(8AF)-substituted or unsubstituted 5 to 6 memberedheteroaryl.

In embodiments, R^(8B) is independently hydrogen, halogen, —CF₃, —CCl₃,—CBr₃, —CI₃, —CN, —OH, —NH₂, —COOH, —CONH₂, —NO₂, —SH, —SO₃H, —SO₄H,—SO₂NH₂, —NHNH₂, —ONH₂, —NHC(O)NHNH₂, —NHC(O)NH₂, —NHSO₂H, —NHC(O)H,—NHC(O)OH, —NHOH, —OCF₃, —OCCl₃, —OCBr₃, —OCI₃, —OCHF₂, —OCHCl₂,—OCHBr₂, —OCHI₂, R^(8BF)-substituted or unsubstituted alkyl,R^(8BF)-substituted or unsubstituted heteroalkyl, R^(8BF)-substituted orunsubstituted cycloalkyl, R^(8BF)-substituted or unsubstitutedheterocycloalkyl, R^(8BF)-substituted or unsubstituted aryl, orR^(8BF)-substituted or unsubstituted heteroaryl. In embodiments, R^(8B)is independently hydrogen, halogen, —CF₃, —CCl₃, —CBr₃, —CI₃, —CN, —OH,—NH₂, —COOH, —CONH₂, —NO₂, —SH, —SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂, —ONH₂,—NHC(O)NHNH₂, —NHC(O)NH₂, —NHSO₂H, —NHC(O)H, —NHC(O)OH, —NHOH, —OCF₃,—OCCl₃, —OCBr₃, —OCI₃, —OCHF₂, —OCHCl₂, —OCHBr₂, —OCHI₂,R^(8BF)-substituted or unsubstituted C₁-C₆ alkyl, R^(8BF)-substituted orunsubstituted 2 to 6 membered heteroalkyl, R^(8BF)-substituted orunsubstituted C₃-C₆ cycloalkyl, R^(8BF)-substituted or unsubstituted 3to 6 membered heterocycloalkyl, R^(8BF)-substituted or unsubstitutedphenyl, or R^(8BF)-substituted or unsubstituted 5 to 6 memberedheteroaryl.

In embodiments, R^(8C) is independently hydrogen, halogen, —CF₃, —CCl₃,—CBr₃, —CI₃, —CN, —OH, —NH₂, —COOH, —CONH₂, —NO₂, —SH, —SO₃H, —SO₄H,—SO₂NH₂, —NHNH₂, —ONH₂, —NHC(O)NHNH₂, —NHC(O)NH₂, —NHSO₂H, —NHC(O)H,—NHC(O)OH, —NHOH, —OCF₃, —OCCl₃, —OCBr₃, —OCI₃, —OCHF₂, —OCHCl₂,—OCHBr₂, —OCHI₂, R^(8CF)-substituted or unsubstituted alkyl,R^(8CF)-substituted or unsubstituted heteroalkyl, R^(8CF)-substituted orunsubstituted cycloalkyl, R^(8CF)-substituted or unsubstitutedheterocycloalkyl, R^(8CF)-substituted or unsubstituted aryl, orR^(8CF)-substituted or unsubstituted heteroaryl. In embodiments, R^(8C)is independently hydrogen, halogen, —CF₃, —CCl₃, —CBr₃, —CI₃, —CN, —OH,—NH₂, —COOH, —CONH₂, —NO₂, —SH, —SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂, —ONH₂,—NHC(O)NHNH₂, —NHC(O)NH₂, —NHSO₂H, —NHC(O)H, —NHC(O)OH, —NHOH, —OCF₃,—OCCl₃, —OCBr₃, —OCI₃, —OCHF₂, —OCHCl₂, —OCHBr₂, —OCHI₂,R^(8CF)-substituted or unsubstituted C₁-C₆ alkyl, R^(8CF)-substituted orunsubstituted 2 to 6 membered heteroalkyl, R^(8CF)-substituted orunsubstituted C₃-C₆ cycloalkyl, R^(8CF)-substituted or unsubstituted 3to 6 membered heterocycloalkyl, R^(8CF)-substituted or unsubstitutedphenyl, or R^(8CF)-substituted or unsubstituted 5 to 6 memberedheteroaryl. R^(8B) and R^(8C) bonded to the same nitrogen atom mayoptionally be joined to form a R^(8CF)-substituted or unsubstituted 3 to6 membered heterocycloalkyl or R^(8CF)-substituted or unsubstituted 5 to6 membered heteroaryl.

In embodiments, R^(8D) is independently hydrogen, halogen, —CF₃, —CCl₃,—CBr₃, —CI₃, —CN, —OH, —NH₂, —COOH, —CONH₂, —NO₂, —SH, —SO₃H, —SO₄H,—SO₂NH₂, —NHNH₂, —ONH₂, —NHC(O)NHNH₂, —NHC(O)NH₂, —NHSO₂H, —NHC(O)H,—NHC(O)OH, —NHOH, —OCF₃, —OCCl₃, —OCBr₃, —OCI₃, —OCHF₂, —OCHCl₂,—OCHBr₂, —OCHI₂, R^(8DF)-substituted or unsubstituted alkyl,R^(8DF)-substituted or unsubstituted heteroalkyl, R^(8DF)-substituted orunsubstituted cycloalkyl, R^(8DF)-substituted or unsubstitutedheterocycloalkyl, R^(8DF)-substituted or unsubstituted aryl, orR^(8DF)-substituted or unsubstituted heteroaryl. In embodiments, R^(8D)is independently hydrogen, halogen, —CF₃, —CCl₃, —CBr₃, —CI₃, —CN, —OH,—NH₂, —COOH, —CONH₂, —NO₂, —SH, —SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂, —ONH₂,—NHC(O)NHNH₂, —NHC(O)NH₂, —NHSO₂H, —NHC(O)H, —NHC(O)OH, —NHOH, —OCF₃,—OCCl₃, —OCBr₃, —OCI₃, —OCHF₂, —OCHCl₂, —OCHBr₂, —OCHI₂,R^(8DF)-substituted or unsubstituted C₁-C₆ alkyl, R^(8DF)-substituted orunsubstituted 2 to 6 membered heteroalkyl, R^(8DF)-substituted orunsubstituted C₃-C₆ cycloalkyl, R^(8DF)-substituted or unsubstituted 3to 6 membered heterocycloalkyl, R^(8DF)-substituted or unsubstitutedphenyl, or R^(8DF)-substituted or unsubstituted 5 to 6 memberedheteroaryl.

In embodiments, R^(9A) is independently hydrogen, halogen, —CF₃, —CCl₃,—CBr₃, —CI₃, —CN, —OH, —NH₂, —COOH, —CONH₂, —NO₂, —SH, —SO₃H, —SO₄H,—SO₂NH₂, —NHNH₂, —ONH₂, —NHC(O)NHNH₂, —NHC(O)NH₂, —NHSO₂H, —NHC(O)H,—NHC(O)OH, —NHOH, —OCF₃, —OCCl₃, —OCBr₃, —OCI₃, —OCHF₂, —OCHCl₂,—OCHBr₂, —OCHI₂, R^(9AF)-substituted or unsubstituted alkyl,R^(9AF)-substituted or unsubstituted heteroalkyl, R^(9AF)-substituted orunsubstituted cycloalkyl, R^(9AF)-substituted or unsubstitutedheterocycloalkyl, R^(9AF)-substituted or unsubstituted aryl, orR^(9AF)-substituted or unsubstituted heteroaryl. In embodiments, R^(9A)is independently hydrogen, halogen, —CF₃, —CCl₃, —CBr₃, —CI₃, —CN, —OH,—NH₂, —COOH, —CONH₂, —NO₂, —SH, —SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂, —ONH₂,—NHC(O)NHNH₂, —NHC(O)NH₂, —NHSO₂H, —NHC(O)H, —NHC(O)OH, —NHOH, —OCF₃,—OCCl₃, —OCBr₃, —OCI₃, —OCHF₂, —OCHCl₂, —OCHBr₂, —OCHI₂,R^(9AF)-substituted or unsubstituted C₁-C₆ alkyl, R^(9AF)-substituted orunsubstituted 2 to 6 membered heteroalkyl, R^(9AF)-substituted orunsubstituted C₃-C₆ cycloalkyl, R^(9AF)-substituted or unsubstituted 3to 6 membered heterocycloalkyl, R^(9AF)-substituted or unsubstitutedphenyl, or R^(9AF)-substituted or unsubstituted 5 to 6 memberedheteroaryl.

In embodiments, R^(9B) is independently hydrogen, halogen, —CF₃, —CCl₃,—CBr₃, —CI₃, —CN, —OH, —NH₂, —COOH, —CONH₂, —NO₂, —SH, —SO₃H, —SO₄H,—SO₂NH₂, —NHNH₂, —ONH₂, —NHC(O)NHNH₂, —NHC(O)NH₂, —NHSO₂H, —NHC(O)H,—NHC(O)OH, —NHOH, —OCF₃, —OCCl₃, —OCBr₃, —OCI₃, —OCHF₂, —OCHCl₂,—OCHBr₂, —OCHI₂, R^(9BF)-substituted or unsubstituted alkyl,R^(9BF)-substituted or unsubstituted heteroalkyl, R^(9BF)-substituted orunsubstituted cycloalkyl, R^(9BF)-substituted or unsubstitutedheterocycloalkyl, R^(9BF)-substituted or unsubstituted aryl, orR^(9BF)-substituted or unsubstituted heteroaryl. In embodiments, R^(9B)is independently hydrogen, halogen, —CF₃, —CCl₃, —CBr₃, —CI₃, —CN, —OH,—NH₂, —COOH, —CONH₂, —NO₂, —SH, —SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂, —ONH₂,—NHC(O)NHNH₂, —NHC(O)NH₂, —NHSO₂H, —NHC(O)H, —NHC(O)OH, —NHOH, —OCF₃,—OCCl₃, —OCBr₃, —OCI₃, —OCHF₂, —OCHCl₂, —OCHBr₂, —OCHI₂,R^(9BF)-substituted or unsubstituted C₁-C₆ alkyl, R^(9BF-)substituted orunsubstituted 2 to 6 membered heteroalkyl, R^(9BF)-substituted orunsubstituted C₃-C₆ cycloalkyl, R^(9BF)-substituted or unsubstituted 3to 6 membered heterocycloalkyl, R^(9BF)-substituted or unsubstitutedphenyl, or R^(9BF)-substituted or unsubstituted 5 to 6 memberedheteroaryl.

In embodiments, R^(9C) is independently hydrogen, halogen, —CF₃, —CCl₃,—CBr₃, —CI₃, —CN, —OH, —NH₂, —COOH, —CONH₂, —NO₂, —SH, —SO₃H, —SO₄H,—SO₂NH₂, —NHNH₂, —ONH₂, —NHC(O)NHNH₂, —NHC(O)NH₂, —NHSO₂H, —NHC(O)H,—NHC(O)OH, —NHOH, —OCF₃, —OCCl₃, —OCBr₃, —OCI₃, —OCHF₂, —OCHCl₂,—OCHBr₂, —OCHI₂, R^(9CF)-substituted or unsubstituted alkyl,R^(9CF)-substituted or unsubstituted heteroalkyl, R^(9CF)-substituted orunsubstituted cycloalkyl, R^(9CF)-substituted or unsubstitutedheterocycloalkyl, R^(9CF)-substituted or unsubstituted aryl, orR^(9CF)-substituted or unsubstituted heteroaryl. In embodiments, R^(9C)is independently hydrogen, halogen, —CF₃, —CCl₃, —CBr₃, —CI₃, —CN, —OH,—NH₂, —COOH, —CONH₂, —NO₂, —SH, —SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂, —ONH₂,—NHC(O)NHNH₂, —NHC(O)NH₂, —NHSO₂H, —NHC(O)H, —NHC(O)OH, —NHOH, —OCF₃,—OCCl₃, —OCBr₃, —OCI₃, —OCHF₂, —OCHCl₂, —OCHBr₂, —OCHI₂,R^(9CF)-substituted or unsubstituted C₁-C₆ alkyl, R^(9CF)-substituted orunsubstituted 2 to 6 membered heteroalkyl, R^(9CF)-substituted orunsubstituted C₃-C₆ cycloalkyl, R^(9CF)-substituted or unsubstituted 3to 6 membered heterocycloalkyl, R^(9CF)-substituted or unsubstitutedphenyl, or R^(9CF)-substituted or unsubstituted 5 to 6 memberedheteroaryl. R^(9B) and R^(9C) bonded to the same nitrogen atom mayoptionally be joined to form a R^(9CF)-substituted or unsubstituted 3 to6 membered heterocycloalkyl or R^(9CF)-substituted or unsubstituted 5 to6 membered heteroaryl.

In embodiments, R^(9D) is independently hydrogen, halogen, —CF₃, —CCl₃,—CBr₃, —CI₃, —CN, —OH, —NH₂, —COOH, —CONH₂, —NO₂, —SH, —SO₃H, —SO₄H,—SO₂NH₂, —NHNH₂, —ONH₂, —NHC(O)NHNH₂, —NHC(O)NH₂, —NHSO₂H, —NHC(O)H,—NHC(O)OH, —NHOH, —OCF₃, —OCCl₃, —OCBr₃, —OCI₃, —OCHF₂, —OCHCl₂,—OCHBr₂, —OCHI₂, R^(9DF)-substituted or unsubstituted alkyl,R^(9DF)-substituted or unsubstituted heteroalkyl, R^(9DF)-substituted orunsubstituted cycloalkyl, R^(9DF)-substituted or unsubstitutedheterocycloalkyl, R^(9DF)-substituted or unsubstituted aryl, orR^(9DF)-substituted or unsubstituted heteroaryl. In embodiments, R^(9D)is independently hydrogen, halogen, —CF₃, —CCl₃, —CBr₃, —CI₃, —CN, —OH,—NH₂, —COOH, —CONH₂, —NO₂, —SH, —SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂, —ONH₂,—NHC(O)NHNH₂, —NHC(O)NH₂, —NHSO₂H, —NHC(O)H, —NHC(O)OH, —NHOH, —OCF₃,—OCCl₃, —OCBr₃, —OCI₃, —OCHF₂, —OCHCl₂, —OCHBr₂, —OCHI₂,R^(9DF)-substituted or unsubstituted C₁-C₆ alkyl, R^(9DF)-substituted orunsubstituted 2 to 6 membered heteroalkyl, R^(9DF)-substituted orunsubstituted C₃-C₆ cycloalkyl, R^(9DF)-substituted or unsubstituted 3to 6 membered heterocycloalkyl, R^(9DF)-substituted or unsubstitutedphenyl, or R^(9DF)-substituted or unsubstituted 5 to 6 memberedheteroaryl.

In embodiments, R^(10A) is independently hydrogen, halogen, —CF₃, —CCl₃,—CBr₃, —CI₃, —CN, —OH, —NH₂, —COOH, —CONH₂, —NO₂, —SH, —SO₃H, —SO₄H,—SO₂NH₂, —NHNH₂, —ONH₂, —NHC(O)NHNH₂, —NHC(O)NH₂, —NHSO₂H, —NHC(O)H,—NHC(O)OH, —NHOH, —OCF₃, —OCCl₃, —OCBr₃, —OCI₃, —OCHF₂, —OCHCl₂,—OCHBr₂, —OCHI₂, R^(10AF)-substituted or unsubstituted alkyl,R^(10AF)-substituted or unsubstituted heteroalkyl, R^(10AF)-substitutedor unsubstituted cycloalkyl, R^(10AF)-substituted or unsubstitutedheterocycloalkyl, R^(10AF)-substituted or unsubstituted aryl, orR^(10AF)-substituted or unsubstituted heteroaryl. In embodiments,R^(10A) is independently hydrogen, halogen, —CF₃, —CCl₃, —CBr₃, —CI₃,—CN, —OH, —NH₂, —COOH, —CONH₂, —NO₂, —SH, —SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂,—ONH₂, —NHC(O)NHNH₂, —NHC(O)NH₂, —NHSO₂H, —NHC(O)H, —NHC(O)OH, —NHOH,—OCF₃, —OCCl₃, —OCBr₃, —OCI₃, —OCHF₂, —OCHCl₂, —OCHBr₂, —OCHI₂,R^(10AF)-substituted or unsubstituted C₁-C₆ alkyl, R^(10AF)-substitutedor unsubstituted 2 to 6 membered heteroalkyl, R^(10AF)-substituted orunsubstituted C₃-C₆ cycloalkyl, R^(10AF)-substituted or unsubstituted 3to 6 membered heterocycloalkyl, R^(10AF)-substituted or unsubstitutedphenyl, or R^(10AF)-substituted or unsubstituted 5 to 6 memberedheteroaryl.

In embodiments, R^(10B) is independently hydrogen, halogen, —CF₃, —CCl₃,—CBr₃, —CI₃, —CN, —OH, —NH₂, —COOH, —CONH₂, —NO₂, —SH, —SO₃H, —SO₄H,—SO₂NH₂, —NHNH₂, —ONH₂, —NHC(O)NHNH₂, —NHC(O)NH₂, —NHSO₂H, —NHC(O)H,—NHC(O)OH, —NHOH, —OCF₃, —OCCl₃, —OCBr₃, —OCI₃, —OCHF₂, —OCHCl₂,—OCHBr₂, —OCHI₂, R^(10BF)-substituted or unsubstituted alkyl,R^(10BF)-substituted or unsubstituted heteroalkyl, R^(10BF)-substitutedor unsubstituted cycloalkyl, R^(10BF)-substituted or unsubstitutedheterocycloalkyl, R^(10BF)-substituted or unsubstituted aryl, orR^(10BF)-substituted or unsubstituted heteroaryl. In embodiments,R^(10B) is independently hydrogen, halogen, —CF₃, —CCl₃, —CBr₃, —CI₃,—CN, —OH, —NH₂, —COOH, —CONH₂, —NO₂, —SH, —SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂,—ONH₂, —NHC(O)NHNH₂, —NHC(O)NH₂, —NHSO₂H, —NHC(O)H, —NHC(O)OH, —NHOH,—OCF₃, —OCCl₃, —OCBr₃, —OCI₃, —OCHF₂, —OCHCl₂, —OCHBr₂, —OCHI₂,R^(10BF)-substituted or unsubstituted C₁-C₆ alkyl, R^(10BF)-substitutedor unsubstituted 2 to 6 membered heteroalkyl, R^(10BF)-substituted orunsubstituted C₃-C₆ cycloalkyl, R^(10BF)-substituted or unsubstituted 3to 6 membered heterocycloalkyl, R^(10BF)-substituted or unsubstitutedphenyl, or R¹° BF-substituted or unsubstituted 5 to 6 memberedheteroaryl.

In embodiments, R^(10C) is independently hydrogen, halogen, —CF₃, —CCl₃,—CBr₃, —CI₃, —CN, —OH, —NH₂, —COOH, —CONH₂, —NO₂, —SH, —SO₃H, —SO₄H,—SO₂NH₂, —NHNH₂, —ONH₂, —NHC(O)NHNH₂, —NHC(O)NH₂, —NHSO₂H, —NHC(O)H,—NHC(O)OH, —NHOH, —OCF₃, —OCCl₃, —OCBr₃, —OCI₃, —OCHF₂, —OCHCl₂,—OCHBr₂, —OCHI₂, R^(10CF)-substituted or unsubstituted alkyl,R^(10CF)-substituted or unsubstituted heteroalkyl, R^(10CF)-substitutedor unsubstituted cycloalkyl, R^(10CF)-substituted or unsubstitutedheterocycloalkyl, R^(10CF)-substituted or unsubstituted aryl, orR^(10CF)-substituted or unsubstituted heteroaryl. In embodiments,R^(10C) is independently hydrogen, halogen, —CF₃, —CCl₃, —CBr₃, —CI₃,—CN, —OH, —NH₂, —COOH, —CONH₂, —NO₂, —SH, —SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂,—ONH₂, —NHC(O)NHNH₂, —NHC(O)NH₂, —NHSO₂H, —NHC(O)H, —NHC(O)OH, —NHOH,—OCF₃, —OCCl₃, —OCBr₃, —OCI₃, —OCHF₂, —OCHCl₂, —OCHBr₂, —OCHI₂,R^(10CF)-substituted or unsubstituted C₁-C₆ alkyl, R^(10CF)-substitutedor unsubstituted 2 to 6 membered heteroalkyl, R^(10CF)-substituted orunsubstituted C₃-C₆ cycloalkyl, R^(10CF)-substituted or unsubstituted 3to 6 membered heterocycloalkyl, R^(10CF)-substituted or unsubstitutedphenyl, or R^(10CF)-substituted or unsubstituted 5 to 6 memberedheteroaryl. R^(10B) and R^(10C) bonded to the same nitrogen atom mayoptionally be joined to form a R^(10CF)-substituted or unsubstituted 3to 6 membered heterocycloalkyl or R^(10CF)-substituted or unsubstituted5 to 6 membered heteroaryl.

In embodiments, R^(10D) is independently hydrogen, halogen, —CF₃, —CCl₃,—CBr₃, —CI₃, —CN, —OH, —NH₂, —COOH, —CONH₂, —NO₂, —SH, —SO₃H, —SO₄H,—SO₂NH₂, —NHNH₂, —ONH₂, —NHC(O)NHNH₂, —NHC(O)NH₂, —NHSO₂H, —NHC(O)H,—NHC(O)OH, —NHOH, —OCF₃, —OCCl₃, —OCBr₃, —OCI₃, —OCHF₂, —OCHCl₂,—OCHBr₂, —OCHI₂, R^(10DF)-substituted or unsubstituted alkyl,R^(10DF)-substituted or unsubstituted heteroalkyl, R^(10DF)-substitutedor unsubstituted cycloalkyl, R^(10DF)-substituted or unsubstitutedheterocycloalkyl, R^(10DF)-substituted or unsubstituted aryl, orR^(10DF)-substituted or unsubstituted heteroaryl. In embodiments,R^(10D) is independently hydrogen, halogen, —CF₃, —CCl₃, —CBr₃, —CI₃,—CN, —OH, —NH₂, —COOH, —CONH₂, —NO₂, —SH, —SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂,—ONH₂, —NHC(O)NHNH₂, —NHC(O)NH₂, —NHSO₂H, —NHC(O)H, —NHC(O)OH, —NHOH,—OCF₃, —OCCl₃, —OCBr₃, —OCI₃, —OCHF₂, —OCHCl₂, —OCHBr₂, —OCHI₂,R^(10DF)-substituted or unsubstituted C₁-C₆ alkyl, R^(10DF)-substitutedor unsubstituted 2 to 6 membered heteroalkyl, R^(10DF)-substituted orunsubstituted C₃-C₆ cycloalkyl, R^(10DF)-substituted or unsubstituted 3to 6 membered heterocycloalkyl, R^(1DF)-substituted or unsubstitutedphenyl, or R^(10DF)-substituted or unsubstituted 5 to 6 memberedheteroaryl.

In embodiments, L¹ is independently R^(11E)-substituted or unsubstitutedC₁-C₃ alkylene.

R^(11E) is independently oxo, halogen, —CF₃, —CCl₃, —CBr₃, —CI₃, —CN,—OH, —NH₂, —COOH, —CONH₂, —NO₂, —SH, —SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂,—ONH₂, —NHC(O)NHNH₂, —NHC(O)NH₂, —NHSO₂H, —NHC(O)H, —NHC(O)OH, —NHOH,—OCF₃, —OCCl₃, —OCBr₃, —OCI₃, —OCHF₂, —OCHCl₂, —OCHBr₂, —OCHI₂,R^(11F)-substituted or unsubstituted alkyl, R^(11F)-substituted orunsubstituted heteroalkyl, R^(11F)-substituted or unsubstitutedcycloalkyl, R^(11F)-substituted or unsubstituted heterocycloalkyl,R^(11F)-substituted or unsubstituted aryl, or R^(11F)-substituted orunsubstituted heteroaryl. In embodiments, R^(11F) is independently oxo,halogen, —CF₃, —CCl₃, —CBr₃, —CI₃, —CN, —OH, —NH₂, —COOH, —CONH₂, —NO₂,—SH, —SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂, —ONH₂, —NHC(O)NHNH₂, —NHC(O)NH₂,—NHSO₂H, —NHC(O)H, —NHC(O)OH, —NHOH, —OCF₃, —OCCl₃, —OCBr₃, —OCI₃,—OCHF₂, —OCHCl₂, —OCHBr₂, —OCHI₂, R^(11F)-substituted or unsubstitutedC₁-C₆ alkyl, R^(11F)-substituted or unsubstituted 2 to 6 memberedheteroalkyl, R^(11F)-substituted or unsubstituted C₃-C₆ cycloalkyl,R^(11F)-substituted or unsubstituted 3 to 6 membered heterocycloalkyl,R^(11F)-substituted or unsubstituted phenyl, or R^(11F)-substituted orunsubstituted 5 to 6 membered heteroaryl.

In embodiments, L² is independently R^(12E)-substituted or unsubstitutedC₁-C₃ alkylene. R^(12E) is independently oxo, halogen, —CF₃, —CCl₃,—CBr₃, —CI₃, —CN, —OH, —NH₂, —COOH, —CONH₂, —NO₂, —SH, —SO₃H, —SO₄H,—SO₂NH₂, —NHNH₂, —ONH₂, —NHC(O)NHNH₂, —NHC(O)NH₂, —NHSO₂H, —NHC(O)H,—NHC(O)OH, —NHOH, —OCF₃, —OCCl₃, —OCBr₃, —OCI₃, —OCHF₂, —OCHCl₂,—OCHBr₂, —OCHI₂, R^(12F)-substituted or unsubstituted alkyl,R^(12F)-substituted or unsubstituted heteroalkyl, R^(12F)-substituted orunsubstituted cycloalkyl, R^(12F)-substituted or unsubstitutedheterocycloalkyl, R^(12F)-substituted or unsubstituted aryl, orR^(12F)-substituted or unsubstituted heteroaryl. In embodiments, R^(12E)is independently oxo, halogen, —CF₃, —CCl₃, —CBr₃, —CI₃, —CN, —OH, —NH₂,—COOH, —CONH₂, —NO₂, —SH, —SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂, —ONH₂,—NHC(O)NHNH₂, —NHC(O)NH₂, —NHSO₂H, —NHC(O)H, —NHC(O)OH, —NHOH, —OCF₃,—OCCl₃, —OCBr₃, —OCI₃, —OCHF₂, —OCHCl₂, —OCHBr₂, —OCHI₂,R^(12F)-substituted or unsubstituted C₁-C₆ alkyl, R^(12F)-substituted orunsubstituted 2 to 6 membered heteroalkyl, R^(12F)-substituted orunsubstituted C₃-C₆ cycloalkyl, R^(12F)-substituted or unsubstituted 3to 6 membered heterocycloalkyl, R^(12F)-substituted or unsubstitutedphenyl, or R^(12F)-substituted or unsubstituted 5 to 6 memberedheteroaryl.

In embodiments, Ar is independently R^(13E)-substituted or unsubstituted(e.g. phenyl) aryl or R^(13E)-substituted or unsubstituted (e.g. 5 to 6membered) heteroaryl. In embodiments, Ar is independentlyR^(13E)-substituted or unsubstituted phenyl or R^(13E)-substituted orunsubstituted 5 to 6 membered heteroaryl. R^(13E) is independently oxo,halogen, —CF₃, —CCl₃, —CBr₃, —CI₃, —CN, —OH, —NH₂, —COOH, —CONH₂, —NO₂,—SH, —SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂, —ONH₂, —NHC(O)NHNH₂, —NHC(O)NH₂,—NHSO₂H, —NHC(O)H, —NHC(O)OH, —NHOH, —OCF₃, —OCCl₃, —OCBr₃, —OCI₃,—OCHF₂, —OCHCl₂, —OCHBr₂, —OCHI₂, R^(13F)-substituted or unsubstitutedalkyl, R^(13F)-substituted or unsubstituted heteroalkyl,R^(13F)-substituted or unsubstituted cycloalkyl, R^(13F)-substituted orunsubstituted heterocycloalkyl, R^(13F)-substituted or unsubstitutedaryl, or R^(13F)-substituted or unsubstituted heteroaryl. Inembodiments, R^(13E) is independently oxo, halogen, —CF₃, —CCl₃, —CBr₃,—CI₃, —CN, —OH, —NH₂, —COOH, —CONH₂, —NO₂, —SH, —SO₃H, —SO₄H, —SO₂NH₂,—NHNH₂, —ONH₂, —NHC(O)NHNH₂, —NHC(O)NH₂, —NHSO₂H, —NHC(O)H, —NHC(O)OH,—NHOH, —OCF₃, —OCCl₃, —OCBr₃, —OCI₃, —OCHF₂, —OCHCl₂, —OCHBr₂, —OCHI₂,R^(13F)-substituted or unsubstituted C₁-C₆ alkyl, R^(13F)-substituted orunsubstituted 2 to 6 membered heteroalkyl, R^(13F)-substituted orunsubstituted C₃-C₆ cycloalkyl, R^(13F)-substituted or unsubstituted 3to 6 membered heterocycloalkyl, R^(13F)-substituted or unsubstitutedphenyl, or R^(13F)-substituted or unsubstituted 5 to 6 memberedheteroaryl.

R^(1F), R^(2F), R^(3F), R^(4F), R^(5F), R^(6F), R^(7F), R^(8F), R^(9F),R^(10F), R^(11F), R^(12F), R^(13F), R^(1AF), R^(1BF), R^(1CF), R^(1DF),R^(2AF), R^(2BF), R^(2CF), R^(2DF), R^(3AF), R^(3BF), R^(3CF), R^(3DF),R^(4AF), R^(4BF), R^(4CF), R^(4DF), R^(5AF), R^(5BF), R^(5CF), R^(5DF),R^(6AF), R^(6BF), R^(6CF), R^(6DF), R^(7AF), R^(7BF), R^(7CF), R^(7DF),R^(8AF), R^(8BF), R^(5CF), R^(8DF), R^(9AF), R^(9BF), R^(9CF), R^(9DF),R^(10AF), R^(10BF), R^(10CF) and R^(10DF) are independently oxo,halogen, —CF₃, —CN, —OH, —NH₂, —COOH, —CONH₂, —NO₂, —SH, —SO₃H, —SO₄H,—SO₂NH₂, —NHNH₂, —ONH₂, —NHC═(O)NHNH₂, —NHC═(O)NH₂, —NHSO₂H, —NHC═(O)H,—NHC(O)—OH, —NHOH, —OCF₃, —OCHF₂, unsubstituted alkyl, unsubstitutedheteroalkyl, unsubstituted cycloalkyl, unsubstituted heterocycloalkyl,unsubstituted aryl, or unsubstituted heteroaryl. In embodiments, R¹,R^(2F), R^(3F), R^(4F), R^(5F), R^(6F), R^(7F), R^(8F), R^(9F), R^(10F),R^(11F), R^(12F), R^(13F), R^(1AF), R^(1BF), R^(1CF), R^(1DF), R^(2AF),R^(2BF), R^(2CF), R^(2DF), R^(3AF), R^(3BF), R^(3CF), R^(3DF), R^(4AF),R^(4BF), R^(4CF), R^(4DF), R^(5AF), R^(5BF), R^(5CF), R^(5DF), R^(6AF),R^(6BF), R^(6CF), R^(6DF), R^(7AF), R^(7BF), R^(7CF), R^(7DF), R^(8AF),R^(8BF), R^(8CF), R^(8DF), R^(9AF), R^(9BF), R^(9CF), R^(9DF), R^(10AF),R^(10BF), R^(10CF) and R^(10DF) are independently oxo, halogen, —CF₃,—CN, —OH, —NH₂, —COOH, —CONH₂, —NO₂, —SH, —SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂,—ONH₂, —NHC═(O)NHNH₂, —NHC═(O)NH₂, —NHSO₂H, —NHC═(O)H, —NHC(O)—OH,—NHOH, —OCF₃, —OCHF₂, unsubstituted C₁-C₆ alkyl, unsubstituted 2 to 6membered heteroalkyl, unsubstituted C₃-C₆ cycloalkyl, unsubstituted 3 to6 membered heterocycloalkyl, unsubstituted phenyl, or unsubstituted 5 to6 membered heteroaryl.

In some embodiments, a compound as described herein may include multipleinstances of R¹, R², R³, R⁴, R⁵, R⁶, R⁷, R⁸, R⁹, R¹, R^(11E), R^(12E),R^(13E), m1, m2, m3, m4, m5, m6, m7, m8, m9, m10, n1, n2, n3, n4, n5,n6, n7, n8, n9, n10, v1, v2, v3, v4, v5, v6, v7, v8, v9, v10 and/orother variables. In such embodiments, each variable may optional bedifferent and be appropriately labeled to distinguish each group forgreater clarity. For example, where each R¹, R², R³, R⁴, R⁵, R⁶, R⁷, R⁸,R⁹, R¹⁰, R^(11E), R^(12E), R^(13E), m1, m2, m3, m4, m5, m6, m7, m8, m9,m10, n1, n2, n3, n4, n5, n6, n7, n8, n9, n10, v1, v2, v3, v4, v5, v6,v7, v8, v9 and/or v10 are different, they may be referred to, forexample, as R^(1.1), R^(1.2), R^(1.3), R^(1.4), R^(1.5), R^(1.6),R^(1.7), R^(2.1), R^(2.2), R^(2.3), R^(2.4), R^(2.5), R^(2.6), R^(2.7),R^(3.1), R^(3.2), R^(3.3), R^(3.4), R^(3.5), R^(3.6), R^(3.7), R^(4.1),R^(4.2), R^(4.3), R^(4.4), R^(4.5), R^(4.6), R^(4.7), R^(5.1), R^(5.2),R^(5.3), R^(5.4), R^(5.5), R^(5.6), R^(5.7), R^(6.1), R^(6.2), R^(6.3),R^(6.4), R^(6.5), R^(6.6), R^(7.1), R^(7.2), R^(7.3), R^(7.4), R^(7.5),R^(7.6), R^(8.1), R^(8.2), R^(8.3), R^(8.4), R^(8.5), R^(8.6), R^(9.1),R^(9.2), R^(9.3), R^(9.4), R^(9.5), R^(9.6), R^(10.1), R^(10.2),R^(10.3), R^(10.4), R^(10.5), R^(10.6), R^(11E.1), R^(11E.2), R^(11E.3),R^(11E.4), R^(11E.5), R^(11E.6), R^(12E.1), R^(12E.2), R^(12E.3),R^(12E.4), R^(12E.5), R^(12E.6), R^(13E.1), R^(13E.2), R^(13E.3),R^(13E.4), R^(13E.5), R^(13E.6), m1¹ m1², m1³, m1⁴, m1⁵, m1⁶, m2¹, m2²,m2³, m2⁴, m2⁵, m2⁶, m3¹, m3², m3³, m3⁴, m3⁵, m3⁶, m4¹, m4², m4³, m4⁴,m4⁵, m4⁶, m5¹, m5², m5³, m5⁴, m5⁵, m5⁶, m6¹, m6², m6³, m6⁴, m6⁵, m6⁶,m7¹, m7², m7³, m7⁴, m7⁵, m7⁶, m8¹, m8², m8³, m8⁴, m8⁵, m8⁶, m9¹, m9²,m9³, m9⁴, m9⁵, m9⁶, m10¹, m10², m10³, m10⁴, m10⁵, m10⁶, n1¹, n1², n1³,n1⁴, n1⁵, n1⁶, n2¹, n2², n2³, n2⁴, n2⁵, n2⁶, n3¹, n3², n3³, n3⁴, n3⁵,n3⁶, n4¹, n4², n4³, n4⁴, n4⁵, n4⁶, n5¹, n5², n5³, n5⁴, n5⁵, n5⁶, n6¹,n6², n6³, n6⁴, n6⁵, n6⁶, n7¹, n7², n7³, n7⁴, n7⁵, n7⁶, n8¹, n8², n8³,n8⁴, n8⁵, n8⁶, n9¹, n9², n9³, n9⁴, n9⁵, n9⁶, n10¹, n10², n10³, n10⁴,n10⁵, n10⁶, v1¹, v1², v1³, v1⁴, v1⁵, v1⁶, v2¹, v2², v2³, v2⁴, v2⁵, v2⁶,v3¹, v3², v3³, v3⁴, v3⁵, v3⁶, v4¹, v4², v4³, v4⁴, v4⁵, v4⁶, v5¹, v5²,v5³, v5⁴, v5⁵, v5⁶, v6¹, v6², v6³, v6⁴, v6⁵, v6⁶, v7¹, v7², v7³, v7⁴,v7⁵, v7⁶, V8¹, V8², v8³, V8⁴, v8⁵, v8⁶, v9¹, v9², v9³, v9⁴, v9⁵, v9⁶,v10¹, v10², v10³, v10⁴, v10⁵, v10⁶, respectively, wherein the definitionof R¹ is assumed by R¹, R^(1.2), R^(1.3), R^(1.4), R^(1.5), R^(1.6),R^(1.7), the definition of R² is assumed by R^(2.1), R^(2.2), R^(2.3),R^(2.4), R^(2.5), R^(2.6), R^(2.7), the definition of R³ is assumed byR^(3.1), R^(3.2), R^(3.3), R^(3.4), R^(3.5), R^(3.6), R^(3.7), thedefinition of R⁴ is assumed by R^(4.1), R^(4.2), R^(4.3), R^(4.4), R⁴⁵,R^(4.6), R⁴⁷, the definition of R⁵ is assumed by R^(5.1), R^(5.2),R^(5.3), R^(5.4), R^(5.5), R^(5.6), R^(5.7), the definition of R⁶ isassumed by R^(6.1), R^(6.2), R^(6.3), R^(6.4), R^(6.5), R^(6.6), thedefinition of R⁷ is assumed by R^(7.1), R^(7.2), R^(7.3), R^(7.4),R^(7.5), R^(7.6), the definition of R⁸ is assumed by R^(8.1), R^(8.2),R^(8.3), R^(8.4), R^(8.5), R^(8.6), the definition of R⁹ is assumed byR^(9.1), R^(9.2), R^(9.3), R^(9.4), R^(9.5), R^(9.6), the definition ofR¹⁰ is assumed by R^(10.1), R^(10.2), R^(10.3), R^(10.4), R^(10.5),R^(10.6), the definition of R^(11E) is assumed by R^(11E.1), R^(11E.2),R^(11E.3), R^(11E.4), R^(11E.5), R^(11E.6), the definition of R^(12E) isassumed by R^(12E.1), R^(12E.2), R^(12E.3), R^(12E.4), R^(12E.5),R^(12E.6), the definition of R^(13E) is assumed by R^(13E.1), R^(13E.2),R^(13E.3), R^(13E.4), R^(13E.5), R^(13E.6), the definition of m1 isassumed by m1, m, m1² m, m1³ m, m14 m1⁵, m1⁶, the definition of m2 isassumed by m2¹, m2², m2³, m2⁴, m2⁵, m2⁶, the definition of m3 is assumedby m3¹, m3², m3³, m3⁴, m3⁵, m3⁶, the definition of m4 is assumed by m4¹,m4², m4³, m4⁴, m4⁵, m4⁶, the definition of m5 is assumed by m5¹, m5²,m5³, m5⁴, m5⁵, m5⁶, the definition of m6 is assumed by m6¹, m6², m6³,m6⁴, m6⁵, m6⁶, the definition of m7 is assumed by m7¹, m7², m7³, m7⁴,m7⁵, m7⁶, the definition of m8 is assumed by m8¹, m8², m8³, m8⁴, m8⁵,m8⁶, the definition of m9 is assumed by m9¹, m9², m9³, m9⁴, m9⁵, m9⁶,the definition of m10 is assumed by m10¹, m10², m10³, m10⁴, m10⁵, m10⁶,the definition of n1 is assumed by n1¹, n1², n1³, n1⁴, n1⁵, n1⁶, thedefinition of n2 is assumed by n2¹, n2², n2³, n2⁴, n2⁵, n2⁶, thedefinition of n3 is assumed by n3¹, n3², n3³, n3⁴, n3⁵, n3⁶, thedefinition of n4 is assumed by n4¹, n4², n4³, n4⁴, n4⁵, n4⁶, thedefinition of n5 is assumed by n5¹, n5², n5³, n5⁴, n5⁵, n5⁶, thedefinition of n6 is assumed by n6¹, n6², n6³, n6⁴, n6⁵, n6⁶, thedefinition of n7 is assumed by n7¹, n7², n7³, n7⁴, n7⁵, n7⁶, thedefinition of n8 is assumed by n8¹, n8², n8³, n8⁴, n8⁵, n8⁶, thedefinition of n9 is assumed by n9¹, n9², n9³, n9⁴, n9⁵, n9⁶, thedefinition of n10 is assumed by n10¹, n10², n10³, n10⁴, n10⁵, n10⁶, thedefinition of v1 is assumed by v1¹, v1², v1³, V1⁴, V1⁵, v1⁶, thedefinition of v2 is assumed by v2¹, v22, v23, v24, v2⁵, v2⁶, thedefinition of v4 is assumed by v3¹, v3², v3³, v3⁴, v3⁵, v3⁶, thedefinition of v4 is assumed by v4¹, v4², v4³, v4⁴, v4⁵, v4⁶, thedefinition of v5 is assumed by v5¹, v5², v5³, v5⁴, v5⁵, v5⁶, thedefinition of v6 is assumed by v6¹, v6², v6³, v6⁴, v6⁵, v6⁶, thedefinition of v7 is assumed by v7¹, v7², v7³, v7⁴, v7⁵, v7⁶, thedefinition of v8 is assumed by v8¹, v8², v8³, v8⁴, v8⁵, v8⁶, thedefinition of v9 is assumed by v9¹, v9², v9³, v9⁴, v9⁵, v9⁶, and thedefinition of v10 is assumed by v10¹, v10², v10³, v10⁴, v10⁵, v10⁶.

The variables used within a definition of R¹, R², R³, R⁴, R⁵, R⁶, R⁷,R⁸, R⁹, R¹⁰, R^(11E), R^(12E), R^(13E), m1, m2, m3, m4, m5, m6, m7, m8,m9, m10, n1, n2, n3, n4, n5, n6, n7, n8, n9, n10, v1, v2, v3, v4, v5,v6, v7, v8, v9, v10 and/or other variables that appear at multipleinstances and are different may similarly be appropriately labeled todistinguish each group for greater clarity.

In embodiments, the compound is:

In embodiments, the compound is:

In embodiments, the compound is a compound described herein (e.g., in anaspect, embodiment, example, table, figure, scheme, appendix, or claim).

II. Pharmaceutical Compositions

Also provided herein are pharmaceutical formulations. In embodiments,the pharmaceutical formulations (e.g. formulae I and IA) include thecompounds described above (including all embodiments thereof) and apharmaceutically acceptable excipient. In one aspect is a pharmaceuticalcomposition that includes a compound of formula I or a pharmaceuticallyacceptable salt thereof and a pharmaceutically acceptable excipient:

wherein L¹, L², Ar, R¹, R², R³, R⁴ and R⁵ are as described herein.

In embodiments, Ar is unsubstituted heteroaryl; L¹ and L² areindependently —CH₂—; and R¹, R², R³, R⁴ and R⁵ are independentlyhydrogen, —OCH₃ or —OCH₂CH₃. In embodiments, R¹, R⁴ and R⁵ are hydrogen.In embodiments, R² and R³ are independently —OCH₃. In embodiments, Ar isunsubstituted 2-thienyl.

Further provided is a pharmaceutical composition, comprising apharmaceutically acceptable excipient, and a compound of Formula IA:

or a pharmaceutically acceptable salt thereof, wherein L, L², Ar, R¹,R², R³, R⁴ and R⁵ are as described herein. In embodiments, L¹ and L² areindependently —CH₂—; and R¹, R², R³, R⁴, R⁵, R⁶, R⁷, R⁸, R⁹ and R¹⁰ areindependently hydrogen, halogen, —OCH₃ or —OCH₂CH₃. In embodiments, L¹and L² are independently —CH₂—; R¹, R², R³, R⁶, R⁷, R⁹ and R¹⁰ areindependently hydrogen, halogen, —OCH₃ or —OCH₂CH₃; and R⁴, R⁵ and R⁸are hydrogen. In embodiments, R² and R³ are independently —OCH₃. Inembodiments, R⁶, R⁷ and R⁹ are independently chlorine or fluorine. Inembodiments, R⁶ is —OCH₂CH₃.

In embodiments, the compound is selected from the group consisting of:

In embodiments, the compound is selected from the group consisting of:

In embodiments of the pharmaceutical compositions, the compound, orpharmaceutically acceptable salt thereof, is included in atherapeutically effective amount.

1. Formulations

The pharmaceutical composition may be prepared and administered in awide variety of dosage formulations. Compounds described may beadministered orally, rectally, or by injection (e.g. intravenously,intramuscularly, intracutaneously, subcutaneously, intraduodenally, orintraperitoneally).

For preparing pharmaceutical compositions from compounds describedherein, pharmaceutically acceptable carriers can be either solid orliquid. Solid form preparations include powders, tablets, pills,capsules, cachets, suppositories, and dispersible granules. A solidcarrier may be one or more substance that may also act as diluents,flavoring agents, binders, preservatives, tablet disintegrating agents,or an encapsulating material.

In powders, the carrier may be a finely divided solid in a mixture withthe finely divided active component. In tablets, the active componentmay be mixed with the carrier having the necessary binding properties insuitable proportions and compacted in the shape and size desired.

The powders and tablets preferably contain from 5% to 70% of the activecompound. Suitable carriers are magnesium carbonate, magnesium stearate,talc, sugar, lactose, pectin, dextrin, starch, gelatin, tragacanth,methylcellulose, sodium carboxymethylcellulose, a low melting wax, cocoabutter, and the like. The term “preparation” is intended to include theformulation of the active compound with encapsulating material as acarrier providing a capsule in which the active component with orwithout other carriers, is surrounded by a carrier, which is thus inassociation with it. Similarly, cachets and lozenges are included.Tablets, powders, capsules, pills, cachets, and lozenges can be used assolid dosage forms suitable for oral administration.

For preparing suppositories, a low melting wax, such as a mixture offatty acid glycerides or cocoa butter, is first melted and the activecomponent is dispersed homogeneously therein, as by stirring. The moltenhomogeneous mixture is then poured into convenient sized molds, allowedto cool, and thereby to solidify.

Liquid form preparations include solutions, suspensions, and emulsions,for example, water or water/propylene glycol solutions. For parenteralinjection, liquid preparations can be formulated in solution in aqueouspolyethylene glycol solution.

Aqueous solutions suitable for oral use can be prepared by dissolvingthe active component in water and adding suitable colorants, flavors,stabilizers, and thickening agents as desired. Aqueous suspensionssuitable for oral use can be made by dispersing the finely dividedactive component in water with viscous material, such as natural orsynthetic gums, resins, methylcellulose, sodium carboxymethylcellulose,and other well-known suspending agents.

Also included are solid form preparations that are intended to beconverted, shortly before use, to liquid form preparations for oraladministration. Such liquid forms include solutions, suspensions, andemulsions. These preparations may contain, in addition to the activecomponent, colorants, flavors, stabilizers, buffers, artificial andnatural sweeteners, dispersants, thickeners, solubilizing agents, andthe like.

The pharmaceutical preparation is preferably in unit dosage form. Insuch form the preparation is subdivided into unit doses containingappropriate quantities of the active component. The unit dosage form canbe a packaged preparation, the package containing discrete quantities ofpreparation, such as packeted tablets, capsules, and powders in vials orampoules. Also, the unit dosage form can be a capsule, tablet, cachet,or lozenge itself, or it can be the appropriate number of any of thesein packaged form.

The quantity of active component in a unit dose preparation may bevaried or adjusted from 0.1 mg to 10000 mg according to the particularapplication and the potency of the active component. The compositioncan, if desired, also contain other compatible therapeutic agents.

Some compounds may have limited solubility in water and therefore mayrequire a surfactant or other appropriate co-solvent in the composition.Such co-solvents include: Polysorbate 20, 60, and 80; Pluronic F-68,F-84, and P-103; cyclodextrin; and polyoxyl 35 castor oil. Suchco-solvents are typically employed at a level between about 0.01% andabout 2% by weight. Viscosity greater than that of simple aqueoussolutions may be desirable to decrease variability in dispensing theformulations, to decrease physical separation of components of asuspension or emulsion of formulation, and/or otherwise to improve theformulation. Such viscosity building agents include, for example,polyvinyl alcohol, polyvinyl pyrrolidone, methyl cellulose, hydroxypropyl methylcellulose, hydroxyethyl cellulose, carboxymethyl cellulose,hydroxy propyl cellulose, chondroitin sulfate and salts thereof,hyaluronic acid and salts thereof, and combinations of the foregoing.Such agents are typically employed at a level between about 0.01% andabout 2% by weight.

The pharmaceutical compositions may additionally include components toprovide sustained release and/or comfort. Such components include highmolecular weight, anionic mucomimetic polymers, gelling polysaccharides,and finely-divided drug carrier substrates. These components arediscussed in greater detail in U.S. Pat. Nos. 4,911,920; 5,403,841;5,212,162; and 4,861,760. The entire contents of these patents areincorporated herein by reference in their entirety for all purposes.

The pharmaceutical composition may be intended for intravenous use. Thepharmaceutically acceptable excipient can include buffers to adjust thepH to a desirable range for intravenous use. Many buffers includingsalts of inorganic acids such as phosphate, borate, and sulfate areknown.

I. Methods of Activating

Further provided herein are methods of activating cystic fibrosistransmembrane regulator (CFTR). In one aspect, the method includescontacting CFTR with an effective amount of a compound of formula I thatcan activate CFTR:

or a pharmaceutically acceptable salt thereof. In compounds of formulaI, L¹, L², Ar, R¹, R², R³, R⁴ and R⁵ are as described herein.

The contacting may be performed in vitro. The contacting may beperformed in vivo.

2. Effective Dosages

The pharmaceutical composition may include compositions wherein theactive ingredient is contained in a therapeutically effective amount,i.e., in an amount effective to achieve its intended purpose. The actualamount effective for a particular application will depend, inter alia,on the condition being treated.

The dosage and frequency (single or multiple doses) of compoundsadministered can vary depending upon a variety of factors, includingroute of administration; size, age, sex, health, body weight, body massindex, and diet of the recipient; nature and extent of symptoms of thedisease being treated; presence of other diseases or otherhealth-related problems; kind of concurrent treatment; and complicationsfrom any disease or treatment regimen. Other therapeutic regimens oragents can be used in conjunction with the methods and compoundsdisclosed herein.

Therapeutically effective amounts for use in humans may be determinedfrom animal models. For example, a dose for humans can be formulated toachieve a concentration that has been found to be effective in animals.The dosage in humans can be adjusted by monitoring response of theconstipation or dry eye to the treatment and adjusting the dosageupwards or downwards, as described above.

Dosages may be varied depending upon the requirements of the subject andthe compound being employed. The dose administered to a subject, in thecontext of the pharmaceutical compositions presented herein, should besufficient to effect a beneficial therapeutic response in the subjectover time. The size of the dose also will be determined by theexistence, nature, and extent of any adverse side effects. Generally,treatment is initiated with smaller dosages, which are less than theoptimum dose of the compound. Thereafter, the dosage is increased bysmall increments until the optimum effect under circumstances isreached.

Dosage amounts and intervals can be adjusted individually to providelevels of the administered compounds effective for the particularclinical indication being treated. This will provide a therapeuticregimen that is commensurate with the severity of the individual'sdisease state.

Utilizing the teachings provided herein, an effective prophylactic ortherapeutic treatment regimen can be planned that does not causesubstantial toxicity and yet is entirely effective to treat the clinicalsymptoms demonstrated by the particular patient. This planning shouldinvolve the careful choice of active compound by considering factorssuch as compound potency, relative bioavailability, patient body weight,presence and severity of adverse side effects, preferred mode ofadministration, and the toxicity profile of the selected agent.

3. Toxicity

The ratio between toxicity and therapeutic effect for a particularcompound is its therapeutic index and can be expressed as the ratiobetween LD₅₀ (the amount of compound lethal in 50% of the population)and ED₅₀ (the amount of compound effective in 50% of the population).Compounds that exhibit high therapeutic indices are preferred.Therapeutic index data obtained from cell culture assays and/or animalstudies can be used in formulating a range of dosages for use in humans.The dosage of such compounds preferably lies within a range of plasmaconcentrations that include the ED₅₀ with little or no toxicity. Thedosage may vary within this range depending upon the dosage formemployed and the route of administration utilized. See, e.g. Fingl etal., In: THE PHARMACOLOGICAL BASIS OF THERAPEUTICS, Ch. 1, p. 1, 1975.The exact formulation, route of administration, and dosage can be chosenby the individual physician in view of the patient's condition and theparticular method in which the compound is used.

When parenteral application is needed or desired, particularly suitableadmixtures for the compounds included in the pharmaceutical compositionmay be injectable, sterile solutions, oily or aqueous solutions, as wellas suspensions, emulsions, or implants, including suppositories. Inparticular, carriers for parenteral administration include aqueoussolutions of dextrose, saline, pure water, ethanol, glycerol, propyleneglycol, peanut oil, sesame oil, polyoxyethylene-block polymers, and thelike. Ampoules are convenient unit dosages. Pharmaceutical admixturessuitable for use in the pharmaceutical compositions presented herein mayinclude those described, for example, in Pharmaceutical Sciences (17thEd., Mack Pub. Co., Easton, Pa.) and WO 96/05309, the teachings of bothof which are hereby incorporated by reference.

II. Methods of Treating

Further provided herein are methods of treating a disease or disorder ina subject in need thereof by administering an effective amount of acompound of formula I:

or a pharmaceutically acceptable salt thereof.

In compounds of formula I, L¹, L², Ar, R¹, R², R³, R⁴ and R⁵ are asdescribed herein.

In one aspect is a method of treating constipation in a subject in needthereof, the method including administering to the subject an effectiveamount of a compound as described herein. In another aspect, is a methodof treating a dry eye disorder in a subject in need thereof, the methodincluding administering to the subject an effective amount of a compoundas described herein. In yet another aspect, is a method of increasinglacrimation in a subject in need thereof, the method includingadministering to the subject an effective amount a compound as describedherein. The constipation may be opioid-induced constipation. Theconstipation may be chronic idiopathic constipation. The constipationmay be irritable bowel syndrome with constipation predominance. The dryeye disorder may be a lacrimal gland disorder.

In one aspect, provided is a method of treating a cholestatic liverdisease in a subject in need thereof, including administering to thesubject an effective amount a compound as described herein. In anotheraspect, provided is a method of treating a pulmonary disease or disorderin a subject in need thereof, including administering to the subject aneffective amount of as described herein. In embodiments, the pulmonarydisease or disorder is chronic obstructive pulmonary disease (e.g.bronchitis, asthma, cigarette smoke-induced lung dysfunction).

Other Aspects

Provided herein, in another aspect, are compositions and methods oftreating a disease. The following definitions and embodiments apply toonly to the compounds of formula (pI), this section and embodimentslisted herein.

For purposes of this section, the term “alkyl” refers to and includeslinear or branched univalent hydrocarbon structures and combinationthereof, which may be fully saturated, mono- or polyunsaturated, havingthe number of carbon atoms designated (i.e., C₁-C₁₀ means one to tencarbons). Particular alkyl groups are those having 1 to 20 carbon atoms(a “C₁-C₂₀ alkyl”). More particular alkyl groups are those having 1 to 8carbon atoms (a “C₁-C₈ alkyl”), 3 to 8 carbon atoms (a “C₃-C₈ alkyl”), 1to 6 carbon atoms (a “C₁-C₆ alkyl”), 1 to 5 carbon atoms (a “C₁-C₅alkyl”), or 1 to 4 carbon atoms (a “C₁-C₄ alkyl”). Examples of saturatedhydrocarbon radicals include, but are not limited to, groups such asmethyl, ethyl, n-propyl, isopropyl, n-butyl, t-butyl, isobutyl,sec-butyl, homologs and isomers of, for example, n-pentyl, n-hexyl,n-heptyl, n-octyl, and the like. An unsaturated alkyl group is onehaving one or more double bonds or triple bonds. Examples of unsaturatedalkyl groups include, but are not limited to, vinyl, 2-propenyl, crotyl,2-isopentenyl, 2-(butadienyl), 2,4-pentadienyl, 3-(1,4-pentadienyl),ethynyl, 1- and 3-propynyl, 3-butynyl, and the higher homologs andisomers. Examples of saturated C₁-C₄ alkyl include methyl (CH₃), ethyl(C₂H₅), propyl (C₃H₇) and butyl (C₄H₉). Examples of saturated C₁-C₆alkyl include methyl (CH₃), ethyl (C₂H₅), propyl (C₃H₇), butyl (C₄H₉),pentyl (C₅H₁₁) and hexyl (C₆H₁₃).

An alkyl group may be substituted (i.e., one or more hydrogen atoms arereplaced with univalent or divalent radicals) with one moresubstituents, such as radicals described herein, for example, fluoro,chloro, bromo, iodo, hydroxyl, alkoxy, thio, amino, acylamino,alkoxycarbonylamino, carboxyl, acyl, alkoxycarbonyl, sulfonyl,cycloalkyl, aryl, heterocyclyl and heteroaryl, and other functionalgroups known in the art. A “perfluoroalkyl” refers to an alkyl groupwhere every hydrogen atom is replaced with a fluorine atom. Examples ofsaturated C₁-C₆ perfluroalkyl include trifluoromethyl (CF₃),pentafluoroethyl (C₂F₅), heptafluoropropyl (C₃F₇), nonafluorobutyl(C₄F₉), undecafluoropentyl (C₅F₁₁) and tridecafluorohexyl (C₆F₁₃).

For purposes of this section, the term “cycloalkyl” refers to andincludes cyclic univalent hydrocarbon structures, which may be fullysaturated, mono- or polyunsaturated, having the number of carbon atomsdesignated (i.e., C₁-C₁₀ means one to ten carbons). Cycloalkyl canconsist of one ring, such as cyclohexyl, or multiple rings, such asadamantly, but excludes aryl groups. A cycloalkyl comprising more thanone ring may be fused, spiro or bridged, or combinations thereof. Apreferred cycloalkyl is a cyclic hydrocarbon having from 3 to 13 annularcarbon atoms. A more preferred cycloalkyl is a cyclic hydrocarbon havingfrom 3 to 8 annular carbon atoms (a “C₃-C₈ cycloalkyl”). Examples ofcycloalkyl include, but are not limited to, cyclopropyl, cyclobutyl,cyclopentyl, cyclohexyl, 1-cyclohexenyl, 3-cyclohexenyl, cycloheptyl,norbornyl, and the like.

For purposes of this section, the term “heterocycle” or “heterocyclyl”refers to a saturated or an unsaturated non-aromatic group having from 1to 10 annular carbon atoms and from 1 to 4 annular heteroatoms, such asnitrogen, sulfur or oxygen, and the like, wherein the nitrogen andsulfur atoms are optionally oxidized, and the nitrogen atom(s) areoptionally quaternized. A heterocyclyl group may have a single ring ormultiple condensed rings, but excludes heteroaryl groups. A heterocyclecomprising more than one ring may be fused, spiro or bridged, or anycombination thereof. In fused ring systems, one or more of the fusedrings can be aryl or heteroaryl. Examples of hetercyclyl groups include,but are not limited to, tetrahydropyranyl, dihydropyranyl, piperidinyl,piperazinyl, pyrrolidinyl, thiazolinyl, thiazolidinyl,tetrahydrofuranyl, tetrahydrothiophenyl,2,3-dihydrobenzo[b]thiophen-2-yl, 4-amino-2-oxopyrimidin-1(2H)-yl, andthe like.

For purposes of this section, the term “aryl” refers to and includespolyunsaturated aromatic hydrocarbon substituents. Aryl may containadditional fused rings (e.g., from 1 to 3 rings), including additionallyfused aryl, heteroaryl, cycloalkyl, and/or heterocyclyl rings. In onevariation, the aryl group contains from 6 to 14 annular carbon atoms.Examples of aryl groups include, but are not limited to, phenyl,naphthyl, biphenyl, and the like.

For purposes of this section, the term “heteroaryl” refers to andincludes unsaturated aromatic cyclic groups having from 1 to 10 annularcarbon atoms and at least one annular heteroatom, including but notlimited to heteroatoms such as nitrogen, oxygen and sulfur, wherein thenitrogen and sulfur atoms are optionally oxidized, and the nitrogenatom(s) are optionally quaternized. A heteroaryl group can be attachedto the remainder of the molecule at an annular carbon or annularheteroatom. Heteroaryl may contain additional fused rings (e.g., from 1to 3 rings), including additionally fused aryl, heteroaryl, cycloalkyl,and/or heterocyclyl rings. Examples of heteroaryl groups include, butare not limited to, pyridyl, pyrimidyl, thiophenyl, furanyl, thiazolyl,and the like.

Cycloalkyl, aryl, heterocyclyl and heteroaryl groups as referred towithin this section may also be substituted with one or moresubstituents, such as radicals detailed herein, for example, fluoro,chloro, bromo, iodo, hydroxyl, alkoxy, thio, amino, acylamino,alkoxycarbonylamido, carboxyl, acyl, alkoxycarbonyl, sulfonyl, alkyl,cycloalkyl, aryl, hetercyclyl and herteroaryl, and other functionalgroups known in the art.

For purposes of this section, the term “pharmaceutically acceptablecarrier” refers to an ingredient in a pharmaceutical formulation, otherthan an active ingredient, which is nontoxic to a subject., Apharmaceutically acceptable carrier includes, but is not limited to, abuffer, excipient, stabilizer, or preservative, such as those known inthe art, for example, described in Remington's Pharmaceutical Sciences16th edition, Osol, A. Ed. (1980).

As used in this section, “treatment” or “treating” is an approach forobtaining beneficial or desired results including and preferablyclinical results. For example, beneficial or desired clinical resultsinclude, but are not limited to, one or more of the following:decreasing symptoms resulting from the disease, increasing the qualityof life of those suffering from the disease, decreasing the dose ofother medications required to treat the disease, delaying theprogression of the disease, and/or prolonging survival of individuals.

As used in this section, the phrase “delaying development of a disease”means to defer, hinder, slow, retard, stabilize, and/or postponedevelopment of the disease (such as constipation or dry eye). This delaycan be of varying lengths of time, depending on the history of thedisease and/or individual being treated. As is evident to one skilled inthe art, a sufficient or significant delay can, in effect, encompassprevention, in that the individual does not develop the disease.

As used in this section, an “effective dosage” or “effective amount” ofdrug, compound, or pharmaceutical composition is an amount sufficient toeffect beneficial or desired results. For prophylactic use, beneficialor desired results include results such as eliminating or reducing therisk, lessening the severity, or delaying the onset of the disease,including biochemical, histological and/or behavioral symptoms of thedisease, its complications and intermediate pathological phenotypespresenting during development of the disease. For therapeutic use,beneficial or desired results include clinical results such asdecreasing one or more symptoms resulting from the disease, increasingthe quality of life of those suffering from the disease, decreasing thedose of other medications required to treat the disease, enhancingeffect of another medication such as via targeting, delaying theprogression of the disease, and/or prolonging survival. An effectivedosage can be administered in one or more administrations. For purposesof this section, an effective dosage of drug, compound, orpharmaceutical composition is an amount sufficient to accomplishprophylactic or therapeutic treatment either directly or indirectly. Asis understood in the clinical context, an effective dosage of a drug,compound, or pharmaceutical composition may or may not be achieved inconjunction with another drug, compound, or pharmaceutical composition.Thus, an “effective dosage” may be considered in the context ofadministering one or more therapeutic agents, and a single agent may beconsidered to be given in an effective amount if, in conjunction withone or more other agents, a desirable result may be or is achieved.

As used in this section, “in conjunction with” refers to administrationof one treatment modality in addition to another treatment modality. Assuch, “in conjunction with” refers to administration of one treatmentmodality before, during or after administration of the other treatmentmodality to the individual.

Unless clearly indicated otherwise, for purposes of this section, theterm “individual” as used herein refers to a mammal, including but notlimited to, bovine, horse, feline, rabbit, canine, rodent, or primate(e.g., human). In some embodiments, an individual is a human. In someembodiments, an individual is a non-human primate such as chimpanzeesand other apes and monkey species. In some embodiments, an individual isa farm animal such as cattle, horses, sheep, goats and swine; pets suchas rabbits, dogs and cats; laboratory animals including rodents, such asrats, mice, and guinea pigs; and the like. The aspects described in thissection may find use in both human medicine and in the veterinarycontext.

As used herein, the singular forms “a,” “an,” and “the” include pluralreference unless the context clearly indicates otherwise.

It is understood that aspect and variations of the aspects described inthis section include “consisting” and/or “consisting essentially of”aspects and variations.

Constipation therapy includes laxatives that increase stool bulk, suchas soluble fiber; create an osmotic load, such as polyethylene glycol;or stimulate intestinal contraction, such as the diphenylmethanes. Thereare also surface laxatives that soften stool such as docusate sodium andprobiotics such as Lactobacillus paracasei [3]. The FDA-approved druglinaclotide, a peptide agonist of the guanylate cyclase C receptor, actsby inhibiting visceral pain, stimulating intestinal motility, andincreasing intestinal secretion [4, 5]. A second approved drug,lubiprostone, a prostaglandin E analog, is thought to activate aputative enterocyte ClC-2 channel [6], though the mechanistic data areless clear. Despite the wide range of therapeutic options, there is acontinued need for safe and effective drugs to treat constipation.

Without wishing to be bound by theory, in embodiments of this section,activation of the cystic fibrosis transmembrane regulator (CFTR)chloride channel drives fluid secretion in the intestine, whichmaintains lubrication of luminal contents. It is hypothesized thatdirect activation of CFTR may cause fluid secretion and reverseexcessive dehydration of stool found in constipation.

Intestinal fluid secretion involves active Cl⁻ secretion across theenterocyte epithelium through the basolateral membrane Na⁺/K⁺/2Cl⁻cotransporter (NKCC1) and the luminal membrane cystic fibrosistransmembrane regulator (CFTR) Cl⁻ channel and Ca²⁺-activated Cl⁻channel (CaCC). The electrochemical and osmotic forces created by Cl⁻secretion drive Na⁺ and water secretion [7]. In cholera and Traveler'sdiarrhea CFTR is strongly activated by bacterial enterotoxins throughelevation of intracellular cyclic nucleotides [8, 9]. CFTR is anattractive target to increase intestinal fluid secretion in constipationas it is robustly expressed throughout the intestine and its activationstrongly increases intestinal fluid secretion. An activator targetingCFTR directly is unlikely to produce the massive, uncontrolledintestinal fluid secretion seen in cholera because the enterotoxins incholera act irreversibly to produce sustained elevation of cytoplasmiccAMP, which not only activates CFTR but also basolateral K⁺ channels,which increase the electrochemical driving force for Cl⁻ secretion;cholera enterotoxins also inhibit the luminal NHE3 Na⁺/H⁺ exchangerinvolved in intestinal fluid absorption [10, 11].

Motivated by these considerations and the continuing need for safe andeffective drug therapy of constipation, the identification andcharacterization of a nanomolar-potency, CFTR-targeted small-moleculeactivators with pro-secretory action in intestine and efficacy inconstipation are reported herein.

By high-throughput screening a nanomolar-affinity, small-molecule CFTRactivator, CFTR_(act)-J027 was identified and demonstrated to havepro-secretory action in mouse intestine and efficacy in normalizingstool output in a loperamide-induced mouse model of constipation.Constipation remains a significant clinical problem in outpatient andhospitalized settings. Opioid-induced constipation is a common adverseeffect in patients after surgery, undergoing chemotherapy and withchronic pain.

CFTR-targeted activation adds to the various mechanisms of action ofanti-constipation therapeutics. It is notable that pure CFTR activationis able to produce a robust Cl⁻ current and fluid secretion response inthe intestine, without causing global elevation of cyclic nucleotideconcentration, direct stimulation of intestinal contractility, oralteration of intestinal fluid absorption. Linaclotide, a peptideagonist of the guanylate cyclase C receptor that increases intestinalcell cGMP concentration. Linaclotide inhibits activation of colonicsensory neurons and activates motor neurons, which reduces pain andincreases intestinal smooth muscle contraction; in addition, elevationin cGMP concentration in enterocytes may activate CFTR and have apro-secretory action [4, 5]. A second approved drug, the prostaglandin Eanalog lubiprostone, is thought to activate a putative enterocyte ClC-2channel [6], though the mechanistic data are less clear. Compared withthese drugs, a pure CFTR activator has a single, well-validatedmechanism of action and does not produce a global cyclic nucleotideresponse in multiple cell types. Of note, linaclotide and lubiprostoneshowed limited efficacy in clinical trials. Linaclotide was effective in˜20% of chronic constipation patients of whom ˜5% also responded toplacebo [15], and lubiprostone was effective in ˜13% of IBS-C patientsof whom ˜7% responded to placebo [16]. Based on our mouse data showingsubstantially greater efficacy of CFTR_(act)-J027 compared tosupramaximal doses of linaclotide or lubiprostone, we speculate thatCFTR activators may have greater efficacy in clinical trials.

CFTR_(act)-J027 is more potent for activation of wildtype CFTR thanVX-770 (ivacaftor), the FDA-approved drug for treatment of cysticfibrosis (CF) caused by certain CFTR gating mutations. In FRT cellsexpressing wild-type CFTR, short-circuit current measurement showednearly full activation of CFTR by CFTR_(act)-J027 at 3 μM whereas VX-770maximally activated CFTR by only 15% (data not shown). However,CFTR_(act)-J027 was substantially less potent than ivacaftor as a‘potentiator’ of defective chloride channel gating of the most commonCF-causing mutation, ΔF508, which is not unexpected, as potentiatorefficacy in CF is mutation-specific. In addition to its potentialtherapeutic utility for constipation, a small-molecule activator ofwildtype CFTR may be useful for treatment of chronic obstructivepulmonary disease and bronchitis, asthma, cigarette smoke-induced lungdysfunction, dry eye and cholestatic liver disease [17-19].

Substituted quinoxalinones were reported as selective antagonists of themembrane efflux transporter multiple-drug-resistance protein 1 [20].Quinoxalinones have also been reported to show anti-diabetic activity bystimulating insulin secretion in pancreatic INS-1 cells [21], andinhibitory activity against serine proteases for potential therapy ofthrombotic disorders [22]. Recently, quinoxalinones have been reportedto inhibit aldose reductase [23]. These reports suggest that thequinoxalinone scaffold has drug-like properties. Synthetically,quinoxalinone can be prepared in one to four steps from commerciallyavailable starting materials [24], which allows facile synthesis oftargeted analogs.

In addition to compound-specific off-target actions, the potentialside-effects profile of a CFTR activator could include pro-secretoryactivity in the airway/lungs and various glandular and other epithelia.Off-target effects for constipation therapy could be limited by oraladministration of a CFTR activator with limited intestinal absorptionand/or rapid systemic clearance to minimize systemic exposure.CFTR_(act)-J027 when administered orally at a high dose (10 mg/kg)showed very low bioavailability with blood levels well below the EC₅₀for CFTR activation, which may be due to first-pass effect as evidencedits rapid in vitro metabolism in liver microsomes. CFTR_(act)-J027 didnot show significant in vitro cytotoxicity at a concentration of 25M, >100-fold greater than its EC₅₀ for CFTR activation, or in vivotoxicity in mice in a 7-day study at a maximal efficacious dose thatnormalized stool output in the loperamide model of constipation. Thepotentially most significant off-target action, stimulation oflung/airway fluid secretion, was not seen as evidenced by normal lungwater content in the 7-day treated mice. These limited toxicity studiesoffer proof of concept for application of a CFTR activator inconstipation.

In summary, the data presented herein demonstrate the pro-secretoryaction of a CFTR activator in mouse intestine for use in treatment ofvarious types of constipation, which could include opioid-inducedconstipation, chronic idiopathic constipation, and irritable bowelsyndrome with constipation predominance.

Dry eye disorders, including Sjögren's syndrome, constitute a commonproblem in the aging population with limited effective therapeuticoptions available. The cAMP-activated Cl⁻ channel CFTR (cystic fibrosistransmembrane conductance regulator) is a major pro-secretory chloridechannel at the ocular surface. It was investigated whether compoundsthat target CFTR can correct the abnormal tear film in dry eye.Small-molecule activators of human wild-type CFTR identified byhigh-throughput screening were evaluated in cell culture and in vivoassays to select compounds that stimulate Cl⁻-driven fluid secretionacross the ocular surface in mice. An aminophenyl-1,3,5-triazine,CFTR_(act)-K089, fully activated CFTR in cell cultures with EC₅₀˜250 nMand produced a ˜8.5 mV hyperpolarization in ocular surface potentialdifference. When delivered topically, CFTR_(act)-K089 doubled basal tearsecretion for four hours and had no effect in CF mice. CFTR_(act)-K089showed sustained tear film bioavailability without detectable systemicabsorption. In a mouse model of aqueous-deficient dry eye produced bylacrimal gland excision, topical administration of 0.1 nmolCFTR_(act)-K089 three times daily restored tear secretion to basallevels and fully prevented the corneal epithelial disruption seen invehicle-treated controls. The data presented herein demonstratepotential utility of CFTR-targeted activators as a novel pro-secretorytreatment for dry eye.

Ninety-four percent of surveyed ophthalmologists believe that additionaltreatments are needed for moderate-to-severe dry eye (7).

The ocular surface is a collection of anatomically continuous epithelialand glandular tissues that are functionally linked to maintain the tearfilm (8). While lacrimation contributes the bulk of reflex tearing, thecornea and conjunctiva regulate basal tear volume and composition. Theprincipal determinants of water movement across the ocular surface intothe tear film include apical chloride (Cl⁻) secretion through cAMP- andcalcium (Ca²⁺)-dependent Cl⁻ transporters, and sodium (Na⁺) absorptionlargely though the epithelial Na⁺ channel (ENaC).

With regard to pro-secretory candidates for dry eye therapy, an ENaCinhibitor, P321, has recently entered phase 1/2 studies (9). Diquafosol,a UTP analog that targets surface epithelial P2Y₂ receptors andstimulates Cl⁻ and mucin secretion by Ca²⁺ signaling (10), is approvedfor dry eye in Japan (11, 12) but failed phase III trials in the UnitedStates.

The cystic fibrosis transmembrane conductance regulator (CFTR) is acAMP-activated Cl⁻ channel expressed in some secretory epithelial cells,including those in cornea and conjunctiva (14-16). We found substantialcapacity for active CFTR-facilitated Cl⁻ at the ocular surface in mice(21, 22), as subsequently shown in rat conjunctiva (23), providing arational basis for investigation of CFTR activators as a pro-secretorystrategy for dry eye. The only clinically approved CFTR activator,VX-770 (ivacaftor), is indicated for potentiating the channel gating ofcertain CFTR mutants causing CF, but only weakly activates wild-typeCFTR (24, 25).

Novel small-molecule activators of wild-type CFTR identified byhigh-throughput screening as potential topical therapy for dry eye wereevaluated to demonstrate efficacy of newly identified CFTR activator(s)in a mouse model of dry eye.

The potential utility of small-molecule activators of CFTR for dry eyetherapy was investigated. After several prior development failures, dryeye remains an unmet need in ocular disease. It was hypothesized thatCFTR-targeted pro-secretory compounds could normalize tear film volumeand ocular surface properties in dry eye (21, 22). In dry eye disorders,tear film hyperosmolarity stimulates pro-inflammatory signaling,secretion of cytokines and metalloproteinases, and disruption of cornealepithelial cell integrity (35-38). By minimizing tear filmhyperosmolarity, CFTR activation is predicted to prevent thesedownstream ocular surface changes.

Small-molecule CFTR activators were identified by high-throughputscreening that produced sustained Cl⁻-driven aqueous fluid secretionacross the ocular surface by a mechanism involving direct CFTRactivation rather than upstream cAMP signaling. The rationale to choosecompounds that activate CFTR directly was to minimize potentialoff-target effects of generalized cAMP stimulation and to reduce thelikelihood of tachyphylaxis for compounds targeting signaling receptors.These compounds had low-nanomolar EC₅₀ for activation of human CFTR invitro and produced full activation at higher concentrations. LargeCFTR-dependent PD hyperpolarizations and tear hypersecretion weredemonstrated in mice. Substantial compound activities in mice and humanswill facilitate translation of data here to humans.

It was found that CFTR_(act)-K089 restored tear secretion and preventedepithelial disruption in an experimental mouse model of lacrimalinsufficiency. CFTR activators may be particularly suited for disordersof the lacrimal gland, such as primary Sjögren's syndrome, bystimulating fluid transport across the intact corneal and conjunctivalepithelia. CFTR activators probably exert their major pro-secretoryeffect at the ocular surface, although there is indirect for CFTRexpression and function in lacrimal gland (39-42). Direct stimulation oflacrimal secretion is unlikely in the studies here because of minimalcompound penetration to lacrimal tissues following topical delivery, andthe demonstrated compound efficacy in a model of lacrimal insufficiency.At the ocular surface, the conjunctiva probably contributes the bulk offluid secretion given its much larger surface area compared to cornea(43).

Alternative pro-secretory therapies targeting different ocular surfaceion channels have been considered. The only FDA-approved CFTR activator,VX-770, was developed as a “potentiator” to treat CF by correcting thechannel gating of certain CFTR mutations (44). However, VX-770 showedrelatively little activity against wild-type CFTR in cell cultures andin mice in vivo. Chronic application of VX-770 may also diminish CFTRfunctional expression (24) and cause cataracts (seen in juvenile rats;ref. 42), which is likely an off-target effect because CFTR is notexpressed in lens.

An indirect agonist of Ca²⁺-activated Cl⁻ channel(s), diquafosol,augments both aqueous and mucin secretion. However, diquafosol failedphase III trials, likely due to transient induced Ca²⁺ elevation and Cl⁻channel activation, producing minimal net fluid secretion. CFTRactivators, which produce sustained tear fluid secretion, overcome thislimitation. CFTR_(act)-K089 and CFTR_(act)-J027 showed favorablepharmacodynamics and could be conveniently administered topicallyseveral times daily in a standard ophthalmic formulation.

The data presented herein show that CFTR activation alone facilitatessustained outward Cl⁻ flux and fluid secretion, suggesting that basal K⁺conductance, without augmented cyclic nucleotide or Ca²⁺ signaling, issufficient to support ocular surface fluid transport. Still, thepotential synergy of a CFTR agonist and a K⁺ channel activator or anENaC inhibitor could be explored to further increase tear secretion fordry eye therapy.

The efficacy of CFTR_(act)-K089 in a clinically relevant mouse model ofaqueous-deficient dry eye disease was demonstrated for topical,pro-secretory CFTR activator therapy to restore basal tear secretion andprevent ocular surface pathology. Compared with immunosuppressiveapproaches, CFTR activation has the advantage of addressing an earlyevent in dry eye pathogenesis. Our data thus support the developmentpotential of CFTR activators as first-in-class dry eye therapy.

Examples herein provide further disclosure on aspects and embodiments ofthis section.

Although the foregoing section has been described in some detail by wayof illustration and example for purposes of clarity of understanding, itis apparent to those skilled in the art that certain minor changes andmodifications will be practiced in light of the above teaching.Therefore, the description and examples should not be construed aslimiting the scope of any invention described herein.

All references cited herein, including patent applications andpublications, are hereby incorporated by reference in their entirety.

Embodiments contemplated herein include embodiments P1 to P20 following.

Embodiment P1

A pharmaceutical composition, comprising a pharmaceutically acceptableexcipient, and a compound of Formula I:

or a pharmaceutically acceptable salt thereof, wherein: Ar issubstituted or unsubstituted aryl or substituted or unsubstitutedheteroaryl; L¹ and L² are independently substituted or unsubstitutedC₁-C₃ alkylene; n1 is an integer from 0 to 4; m1 and v1 areindependently 1 or 2; R¹ is hydrogen, halogen, —CX^(1.1) ₃, —CHX^(1.1)₂, —CH₂X^(1.1), —CN, —SO_(n1)R^(1A), —SO_(v1)NR^(1B)R^(1C),—NHNR^(1B)R^(1C), —ONR^(1B)R^(1C), —NHC(O)NHNR^(1B)R^(1C),—NHC(O)NR^(1B)R^(1C), —N(O)_(m1), —NR^(1B)R^(1C), —C(O)R^(1D),—C(O)OR^(1D), —C(O)NR^(1B)R^(1C), —OR^(1A), —NR^(1B)SO₂R^(1A),—NR^(1B)C(O)R^(1D), —NR^(1B)C(O)OR^(1D), —NR^(1B)OR^(1D), —OCX^(1.1) ₃,—OCHX^(1.1) ₂, substituted or unsubstituted alkyl, substituted orunsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl,substituted or unsubstituted heterocycloalkyl, substituted orunsubstituted aryl, or substituted or unsubstituted heteroaryl; R² ishydrogen, halogen, —CX^(2.1) ₃, —CHX^(2.1) ₂, —CH₂X^(2.1), —CN,—SO_(n1)R^(2A), —SO_(v1)NR^(2B)R^(2C), —NHNR^(2B)R^(2C),—ONR^(2B)R^(2C), —NHC(O)NHNR^(2B)R^(2C), —NHC(O)NR^(2B)R^(2C),—N(O)_(m1), —NR^(2B)R^(2C), —C(O)R^(2D), —C(O)OR^(2D),—C(O)NR^(2B)R^(2C), —OR^(2A), —NR^(2B)SO₂R^(2A), —NR^(2B)C(O)R^(2D),—NR^(2B)C(O)OR^(2D), —NR^(2B)OR^(2D), —OCX^(2.1) ₃, —OCHX^(2.1) ₂,substituted or unsubstituted alkyl, substituted or unsubstitutedheteroalkyl, substituted or unsubstituted cycloalkyl, substituted orunsubstituted heterocycloalkyl, substituted or unsubstituted aryl, orsubstituted or unsubstituted heteroaryl; R³ is hydrogen, halogen,—CX^(3.1) ₃, —CHX^(3.1) ₂, —CH₂X^(3.1), —CN, —SO_(n1)R^(3A),—SO_(v1)NR^(3B)R^(3C), —NHNR^(3B)R^(3C), —ONR^(3B)R^(3C),—NHC(O)NHNR^(3B)R^(3C), —NHC(O)NR^(3B)R^(3C), —N(O)_(m1),—NR^(3B)R^(3C), —C(O)R^(3D), —C(O)OR^(3D), —C(O)NR^(3B)R^(3C), —OR^(3A),—NR^(3B)SO₂R^(3A), —NR^(3B)C(O)R^(3D), —NR^(3B)C(O)OR^(3D),—NR^(3B)OR^(3D), —OCX^(3.1) ₃, —OCHX^(3.1) ₂, substituted orunsubstituted alkyl, substituted or unsubstituted heteroalkyl,substituted or unsubstituted cycloalkyl, substituted or unsubstitutedheterocycloalkyl, substituted or unsubstituted aryl, or substituted orunsubstituted heteroaryl; R⁴ is hydrogen, halogen, —CX^(4.1) ₃,—CHX^(4.1) ₂, —CH₂X^(4.1), —CN, —SO_(n1)R^(4A), —SO_(v1)NR^(4B)R^(4C),—NHNR^(4B)R^(4C), —ONR^(4B)R^(4C), —NHC(O)NHNR^(4B)R^(4C),—NHC(O)NR^(4B)R^(4C), —N(O)_(m1), —NR^(4B)R^(4C), —C(O)R^(4D),—C(O)OR^(4D), —C(O)NR^(4B)R^(4C), —OR^(4A), —NR^(4B)SO₂R^(4A),—NR^(4B)C(O)R^(4D), —NR^(4B)C(O)OR^(4D), —NR^(4B)OR^(4D), —OCX^(4.1) ₃,—OCHX^(4.1) ₂, substituted or unsubstituted alkyl, substituted orunsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl,substituted or unsubstituted heterocycloalkyl, substituted orunsubstituted aryl, or substituted or unsubstituted heteroaryl; R⁵ ishydrogen, halogen, —CX^(5.1) ₃, —CHX^(5.1) ₂, —CH₂X^(5.1), —CN,—SO_(n1)R^(5A), —SO_(v1)NR^(5B)R^(5C), —NHNR^(5B)R^(5C),—ONR^(5B)R^(5C), —NHC(O)NHNR^(5B)R^(5C), —NHC(O)NR^(5B)R^(5C),—N(O)_(m1), —NR^(5B)R^(5C), —C(O)R^(5D), —C(O)OR^(5D),—C(O)NR^(5B)R^(5C), —OR^(5A), —NR^(5B)SO₂R^(5A), —NR^(5B)C(O)R^(5D),—NR^(5B)C(O)OR^(5D), —NR^(5B)OR^(5D), —OCX^(5.1) ₃, —OCHX^(5.1) ₂,substituted or unsubstituted alkyl, substituted or unsubstitutedheteroalkyl, substituted or unsubstituted cycloalkyl, substituted orunsubstituted heterocycloalkyl, substituted or unsubstituted aryl, orsubstituted or unsubstituted heteroaryl; R^(1A), R^(1B), R^(1C), R^(1D),R^(2A), R^(2B), R^(2C), R^(2D), R^(3A), R^(3B), R^(3C), R^(3D), R^(4A),R^(4B), R^(4C), R^(4D), R^(5A), R^(5B), R^(5C) and R^(5D) areindependently hydrogen, halogen, —CF₃, —CCl₃, —CBr₃, —CI₃, —OH, —NH₂,—COOH, —CONH₂, —NO₂, —SH, —SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂, —ONH₂,—NHC(O)NHNH₂, —NHC(O)NH₂, —NHSO₂H, —NHC(O)H, —NHC(O)—OH, —NHOH, —OCF₃,—OCCl₃, —OCBr₃, —OCI₃, —OCHF₂, —OCHCl₂, —OCHBr₂, —OCHI₂, substituted orunsubstituted alkyl, substituted or unsubstituted heteroalkyl,substituted or unsubstituted cycloalkyl, substituted or unsubstitutedheterocycloalkyl, substituted or unsubstituted aryl, or substituted orunsubstituted heteroaryl; R^(1B), R^(1C), R^(2B), R^(2C), R^(3B),R^(3C), R^(4B), R^(4C), R^(5B) and R^(5C) substituents bonded to thesame nitrogen atom may optionally be joined to form a substituted orunsubstituted heterocycloalkyl or substituted or unsubstitutedheteroaryl; and X^(1.1), X^(2.1), X^(3.1), X^(4.1) and X^(5.1) areindependently —Cl, —Br, —I or —F.

Embodiment P2

The pharmaceutical composition of embodiment P1, wherein: Ar isunsubstituted heteroaryl; L¹ and L² are independently —CH₂—; and R¹, R²,R³, R⁴ and R⁵ are independently hydrogen, —OCH₃ or —OCH₂CH₃.

Embodiment P3

The pharmaceutical composition of embodiment P2, wherein R¹, R⁴ and R⁵are independently hydrogen.

Embodiment P4

The pharmaceutical composition of embodiment P3, wherein R² and R³ areindependently —OCH₃.

Embodiment P5

The pharmaceutical composition of embodiment P4, wherein Ar isunsubstituted 2-thienyl.

Embodiment P6

A pharmaceutical composition, comprising a pharmaceutically acceptableexcipient, and a compound of Formula IA:

or a pharmaceutically acceptable salt thereof, wherein: Ar issubstituted or unsubstituted aryl or substituted or unsubstitutedheteroaryl; L¹ and L² are independently substituted or unsubstitutedC₁-C₃ alkylene; n1 is an integer from 0 to 4; m1 and v1 areindependently 1 or 2; R¹ is hydrogen, halogen, —CX^(1.1) ₃, —CHX^(1.1)₂, —CH₂X^(1.1), —CN, —SO_(n1)R^(1A), —SO_(v1)NR^(1B)R^(1C),—NHNR^(1B)R^(1C), —ONR^(1B)R^(1C), —NHC(O)NHNR^(1B)R^(1C),—NHC(O)NR^(1B)R^(1C), —N(O)_(m1), —NR^(1B)R^(1C), —C(O)R^(1D),—C(O)OR^(1D), —C(O)NR^(1B)R^(1C), —OR^(1A), —NR^(1B)SO₂R^(1A),—NR^(1B)C(O)R^(1D), —NR^(1B)C(O)OR^(1D), —NR^(1B)OR^(1D), —OCX^(1.1) ₃,—OCHX^(1.1) ₂, substituted or unsubstituted alkyl, substituted orunsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl,substituted or unsubstituted heterocycloalkyl, substituted orunsubstituted aryl, or substituted or unsubstituted heteroaryl; R² ishydrogen, halogen, —CX^(2.1) ₃, —CHX^(2.1) ₂, —CH₂X^(2.1), —CN,—SO_(n1)R^(2A), —SO_(v1)NR^(2B)R^(2C), —NHNR^(2B)R^(2C),—ONR^(2B)R^(2C), —NHC(O)NHNR^(2B)R^(2C), —NHC(O)NR^(2B)R^(2C),—N(O)_(m1), —NR^(2B)R^(2C), —C(O)R^(2D), —C(O)OR^(2D),—C(O)NR^(2B)R^(2C), —OR^(2A), —NR^(2B)SO₂R^(2A), —NR^(2B)C(O)R^(2D),—NR^(2B)C(O)OR^(2D), —NR^(2B)OR^(2D), —OCX^(2.1) ₃, —OCHX^(2.1) ₂,substituted or unsubstituted alkyl, substituted or unsubstitutedheteroalkyl, substituted or unsubstituted cycloalkyl, substituted orunsubstituted heterocycloalkyl, substituted or unsubstituted aryl, orsubstituted or unsubstituted heteroaryl; R³ is hydrogen, halogen,—CX^(3.1) ₃, —CHX^(3.1) ₂, —CH₂X^(3.1), —CN, —SO_(n1)R^(3A),—SO_(v1)NR^(3B)R^(3C), —NHNR^(3B)R^(3C), —ONR^(3B)R^(3C),—NHC(O)NHNR^(3B)R^(3C), —NHC(O)NR^(3B)R^(3C), —N(O)_(m1),—NR^(3B)R^(3C), —C(O)R^(3D), —C(O)OR^(3D), —C(O)NR^(3B)R^(3C), —OR^(3A),—NR^(3B)SO₂R^(3A), —NR^(3B)C(O)R^(3D), —NR^(3B)C(O)OR^(3D),—NR^(3B)OR^(3D), —OCX^(3.1) ₃, —OCHX^(3.1) ₂, substituted orunsubstituted alkyl, substituted or unsubstituted heteroalkyl,substituted or unsubstituted cycloalkyl, substituted or unsubstitutedheterocycloalkyl, substituted or unsubstituted aryl, or substituted orunsubstituted heteroaryl; R⁴ is hydrogen, halogen, —CX^(4.1) ₃,—CHX^(4.1) ₂, —CH₂X^(4.1), —CN, —SO_(n1)R^(4A), —SO_(v1)NR^(4B)R^(4C),—NHNR^(4B)R^(4C), —ONR^(4B)R^(4C), —NHC(O)NHNR^(4B)R^(4C),—NHC(O)NR^(4B)R^(4C), —N(O)_(m1), —NR^(4B)R^(4C), —C(O)R^(4D),—C(O)OR^(4D), —C(O)NR^(4B)R^(4C), —OR^(4A), —NR^(4B)SO₂R^(4A),—NR^(4B)C(O)R^(4D), —NR^(4B)C(O)OR^(4D), —NR^(4B)OR^(4D), —OCX^(4.1) ₃,—OCHX^(4.1) ₂, substituted or unsubstituted alkyl, substituted orunsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl,substituted or unsubstituted heterocycloalkyl, substituted orunsubstituted aryl, or substituted or unsubstituted heteroaryl; R⁵ ishydrogen, halogen, —CX^(5.1) ₃, —CHX^(5.1) ₂, —CH₂X^(5.1), —CN,—SO_(n1)R^(5A), —SO_(v1)NR^(5B)R^(5C), —NHNR^(5B)R^(5C),—ONR^(5B)R^(5C), —NHC(O)NHNR^(5B)R^(5C), —NHC(O)NR^(5B)R^(5C),—N(O)_(m1), —NR^(5B)R^(5C), —C(O)R^(5D), —C(O)OR^(5D),—C(O)NR^(5B)R^(5C), —OR^(5A), —NR^(5B)SO₂R^(5A), —NR^(5B)C(O)R^(5D),—NR^(5B)C(O)OR^(5D), —NR^(5B)OR^(5D), —OCX^(5.1) ₃, —OCHX^(5.1) ₂,substituted or unsubstituted alkyl, substituted or unsubstitutedheteroalkyl, substituted or unsubstituted cycloalkyl, substituted orunsubstituted heterocycloalkyl, substituted or unsubstituted aryl, orsubstituted or unsubstituted heteroaryl; R⁶ is hydrogen, halogen,—CX^(6.1) ₃, —CHX^(6.1) ₂, —CH₂X^(6.1), —CN, —SO_(n1)R^(6A),—SO_(v1)NR^(6B)R^(6C), —NHNR^(6B)R^(6C), —ONR^(6B)R^(6C),—NHC(O)NHNR^(6B)R^(6C), —NHC(O)NR^(6B)R^(6C), —N(O)_(m1), NR^(6B)R^(6C),—C(O)R^(6D), —C(O)OR^(6D), —C(O)NR^(6B)R^(6C), —OR^(6A),—NR^(6B)SO₂R^(6A), —NR^(6B)C(O)R^(6D), —NR^(6B)C(O)OR^(6D),—NR^(6B)OR^(6D), —OCX^(6.1) ₃, —OCHX^(6.1) ₂, substituted orunsubstituted alkyl, substituted or unsubstituted heteroalkyl,substituted or unsubstituted cycloalkyl, substituted or unsubstitutedheterocycloalkyl, substituted or unsubstituted aryl, or substituted orunsubstituted heteroaryl; R⁷ is hydrogen, halogen, —CX^(7.1) ₃,—CHX^(7.1) ₂, —CH₂X^(7.1), —CN, —SO_(n1)R^(7A), —SO_(v1)NR^(7B)R^(7C),—NHNR^(7B)R^(7C), —ONR^(7B)R^(7C), —NHC(O)NHNR^(7B)R^(7C),—NHC(O)NR^(7B)R^(7C), —N(O)_(m1), —NR^(7B)R^(7C), —C(O)R^(7D),—C(O)OR^(7D), —C(O)NR^(7B)R^(7C), —OR^(7A), —NR^(7B)SO₂R^(7A),—NR^(7A)C(O)R^(7C), —NR^(7B)C(O)OR^(7D), —NR^(7B)OR^(7D), —OCX^(7.1) ₃,—OCHX^(7.1) ₂, substituted or unsubstituted alkyl, substituted orunsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl,substituted or unsubstituted heterocycloalkyl, substituted orunsubstituted aryl, or substituted or unsubstituted heteroaryl; R⁸ ishydrogen, halogen, —CX^(8.1) ₃, —CHX^(8.1) ₂, —CH₂X^(8.1), —CN,—SO_(n1)R^(8A), —SO_(v1)NR^(8B)R^(8C), —NHNR^(8B)R^(8C),—ONR^(8B)R^(8C), —NHC(O)NHNR^(8B)R^(8C), —NHC(O)NR^(8B)R^(8C),—N(O)_(m1), —NR^(8B)R^(8C), —C(O)R^(8D), —C(O)OR^(8D),—C(O)NR^(8B)R^(8C), —OR^(8A), —NR^(8B)SO₂R^(8A), —NR^(8B)C(O)R^(8D),—NR^(8B)C(O)OR^(8D), —NR^(8B)OR^(8D), —OCX^(8.1) ₃, —OCHX^(8.1) ₂,substituted or unsubstituted alkyl, substituted or unsubstitutedheteroalkyl, substituted or unsubstituted cycloalkyl, substituted orunsubstituted heterocycloalkyl, substituted or unsubstituted aryl, orsubstituted or unsubstituted heteroaryl; R⁹ is hydrogen, halogen,—CX^(9.1) ₃, —CHX^(9.1) ₂, —CH₂X^(9.1), —CN, —SO_(n1)R^(9A),—SO_(v1)NR^(9B)R^(9C), —NHNR^(9B)R^(9C), —ONR^(9B)R^(9C),—NHC(O)NHNR^(9B)R^(9C), —NHC(O)NR^(9B)R^(9C), —N(O)_(m1),—NR^(9B)R^(9C), —C(O)R^(9D), —C(O)OR^(9D), —C(O)NR^(9B)R⁹C, —OR^(9A),—NR^(9B)SO₂R^(9A), —NR^(9B)C(O)R^(9D), —NR^(9B)C(O)OR^(9D),—NR^(9B)OR^(9D), —OCX^(9.1) ₃, —OCHX^(9.1) ₂, substituted orunsubstituted alkyl, substituted or unsubstituted heteroalkyl,substituted or unsubstituted cycloalkyl, substituted or unsubstitutedheterocycloalkyl, substituted or unsubstituted aryl, or substituted orunsubstituted heteroaryl; R¹⁰ is hydrogen, halogen, —CX^(10.1) ₃,—CHX^(10.1) ₂, —CH₂X^(10.1), —CN, —SO_(n1)R^(10A),—SO_(v1)NR^(10B)R^(10C), —NHNR^(10B)R^(10C), —ONR^(10B)R^(10C),—NHC(O)NHNR^(10B)R^(10C), —NHC(O)NR^(10B)R^(10C), —N(O)_(m1),—NR^(10B)R^(10C), —C(O)R^(10D), —C(O)OR^(10D), —C(O)NR^(10B)R^(10C),OR^(10A), —NR^(10B)SO₂R^(10A), —NR^(10B)C(O)R^(10D),—NR^(10B)C(O)OR^(10D), —NR^(10B)OR^(10D), —OCX^(10.1) ₃, —OCHX^(10.1) ₂,substituted or unsubstituted alkyl, substituted or unsubstitutedheteroalkyl, substituted or unsubstituted cycloalkyl, substituted orunsubstituted heterocycloalkyl, substituted or unsubstituted aryl, orsubstituted or unsubstituted heteroaryl; R^(1A), R^(1B), R^(1C), R^(1D),R^(2A), R^(2B), R^(2C), R^(2D), R^(3A), R^(3B), R^(3C), R^(3D), R^(4A),R^(4B), R^(4C), R^(4D), R^(5A), R^(5B), R^(5C), R^(5D), R^(6A), R^(6B),R^(6C), R^(6D), R^(7A), R^(7B), R^(7C), R^(7D), R^(8A), R^(8B), R^(8C),R^(8D), R^(9A), R^(9B), R^(9C), R^(9D), R^(10A), R^(10B), R^(10C) andR^(10D) are independently hydrogen, halogen, —CF₃, —CCl₃, —CBr₃, —CI₃,—OH, —NH₂, —COOH, —CONH₂, —NO₂, —SH, —SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂,—ONH₂, —NHC(O)NHNH₂, —NHC(O)NH₂, —NHSO₂H, —NHC(O)H, —NHC(O)—OH, —NHOH,—OCF₃, —OCCl₃, —OCBr₃, —OCI₃, —OCHF₂, —OCHCl₂, —OCHBr₂, —OCHI₂,substituted or unsubstituted alkyl, substituted or unsubstitutedheteroalkyl, substituted or unsubstituted cycloalkyl, substituted orunsubstituted heterocycloalkyl, substituted or unsubstituted aryl, orsubstituted or unsubstituted heteroaryl; R^(1B), R^(1C), R^(2B), R^(2C),R^(3B), R^(3C), R^(4B)R^(4C), R^(5B), R^(5C), R^(6B), R^(6C), R^(7B),R^(7C), R^(8B), R^(8C), R^(9B), R^(9C), R^(10B) and R^(10C) substituentsbonded to the same nitrogen atom may optionally be joined to form asubstituted or unsubstituted heterocycloalkyl or substituted orunsubstituted heteroaryl; and X¹, X^(2.1), X^(3.1), X^(4.1), X^(5.1),X^(6.1) X^(7.1), X^(8.1), X^(9.1) and X^(10.1) are independently —Cl,—Br, —I or —F.

Embodiment P7

The pharmaceutical composition of embodiment P6, wherein: L¹ and L² areindependently —CH₂—; and R¹, R², R³, R⁴, R⁵, R⁶, R⁷, R⁸, R⁹ and R¹⁰ areindependently hydrogen, halogen, —OCH₃ or —OCH₂CH₃.

Embodiment P8

The pharmaceutical composition of embodiment P6, wherein: L¹ and L² areindependently —CH₂—; R¹, R², R³, R⁶, R⁷, R⁹ and R¹⁰ are independentlyhydrogen, halogen, —OCH₃ or —OCH₂CH₃; and R⁴, R⁵ and R⁸ areindependently hydrogen.

Embodiment P9

The pharmaceutical composition of embodiment P8, wherein R² and R³ areindependently —OCH₃.

Embodiment P10

The pharmaceutical composition of embodiment P9, wherein R⁶, R⁷ and R⁹are independently chlorine or fluorine.

Embodiment P11

The pharmaceutical composition of embodiment P9, wherein R⁶ is —OCH₂CH₃.

Embodiment P12

A method of treating constipation, comprising administering to a subjectin need thereof a therapeutically effective amount a compound ofstructural Formula (I):

or a pharmaceutically acceptable salt thereof, wherein: Ar issubstituted or unsubstituted aryl or substituted or unsubstitutedheteroaryl; L¹ and L² are independently substituted or unsubstitutedC₁-C₃ alkylene; n1 is an integer from 0 to 4; m1 and v1 areindependently 1 or 2; R¹ is hydrogen, halogen, —CX^(1.1) ₃, —CHX^(1.1)₂, —CH₂X^(1.1), —CN, —SO_(n1)R^(1A), —SO_(v1)NR^(1B)R^(1C),—NHNR^(1B)R^(1C), —ONR^(1B)R^(1C), —NHC(O)NHNR^(1B)R^(1C),—NHC(O)NR^(1B)R^(1C), —N(O)_(m1), —NR^(1B)R^(1C), —C(O)R^(1D),—C(O)OR^(1D), —C(O)NR^(1B)R^(1C), —OR^(1A), —NR^(1B)SO₂R^(1A),—NR^(1B)C(O)R^(1D), —NR^(1B)C(O)OR^(1D), —NR^(1B)OR^(1D), —OCX^(1.1) ₃,—OCHX^(1.1) ₂, substituted or unsubstituted alkyl, substituted orunsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl,substituted or unsubstituted heterocycloalkyl, substituted orunsubstituted aryl, or substituted or unsubstituted heteroaryl; R² ishydrogen, halogen, —CX^(2.1) ₃, —CHX^(2.1) ₂, —CH₂X^(2.1), —CN,—SO_(n1)R^(2A), —SO_(v1)NR^(2B)R^(2C), —NHNR^(2B)R^(2C),—ONR^(2B)R^(2C), —NHC(O)NHNR^(2B)R^(2C), —NHC(O)NR^(2B)R^(2C),—N(O)_(m1), —NR^(2B)R^(2C), —C(O)R^(2D), —C(O)OR^(2D),—C(O)NR^(2B)R^(2C), —OR^(2A), —NR^(2B)SO₂R^(2A), —NR^(2B)C(O)R^(2D),—NR^(2B)C(O)OR^(2D), —NR^(2B)OR^(2D), —OCX^(2.1) ₃, —OCHX^(2.1) ₂,substituted or unsubstituted alkyl, substituted or unsubstitutedheteroalkyl, substituted or unsubstituted cycloalkyl, substituted orunsubstituted heterocycloalkyl, substituted or unsubstituted aryl, orsubstituted or unsubstituted heteroaryl; R³ is hydrogen, halogen,—CX^(3.1) ₃, —CHX^(3.1) ₂, —CH₂X^(3.1), —CN, —SO_(n1)R^(3A),—SO_(v1)NR^(3B)R^(3C), —NHNR^(3B)R^(3C), —ONR^(3B)R^(3C),—NHC(O)NHNR^(3B)R^(3C), —NHC(O)NR^(3B)R^(3C), —N(O)_(m1),—NR^(3B)R^(3C), —C(O)R^(3D), —C(O)OR^(3D), —C(O)NR^(3B)R^(3C), —OR^(3A),—NR^(3B)SO₂R^(3A), —NR^(3B)C(O)R^(3D), —NR^(3B)C(O)OR^(3D),—NR^(3B)OR^(3D), —OCX^(3.1) ₃, —OCHX^(3.1) ₂, substituted orunsubstituted alkyl, substituted or unsubstituted heteroalkyl,substituted or unsubstituted cycloalkyl, substituted or unsubstitutedheterocycloalkyl, substituted or unsubstituted aryl, or substituted orunsubstituted heteroaryl; R⁴ is hydrogen, halogen, —CX^(4.1) ₃,—CHX^(4.1) ₂, —CH₂X^(4.1), —CN, —SO_(n1)R^(4A), —SO_(v1)NR^(4B)R^(4C),—NHNR^(4B)R^(4C), —ONR^(4B)R^(4C), —NHC(O)NHNR^(4B)R^(4C),—NHC(O)NR^(4B)R^(4C), —N(O)_(m1), —NR^(4B)R^(4C), —C(O)R^(4D),—C(O)OR^(4D), —C(O)NR^(4B)R^(4C), —OR^(4A), —NR^(4B)SO₂R^(4A),—NR^(4B)C(O)R^(4D), —NR^(4B)C(O)OR^(4D), —NR^(4B)OR^(4D), —OCX^(4.1) ₃,—OCHX^(4.1) ₂, substituted or unsubstituted alkyl, substituted orunsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl,substituted or unsubstituted heterocycloalkyl, substituted orunsubstituted aryl, or substituted or unsubstituted heteroaryl; R⁵ ishydrogen, halogen, —CX^(5.1) ₃, —CHX^(5.1) ₂, —CH₂X^(5.1), —CN,—SO_(n1)R^(5A), —SO_(v1)NR^(5B)R^(5C), —NHNR^(5B)R^(5C),—ONR^(5B)R^(5C), —NHC(O)NHNR^(5B)R^(5C), —NHC(O)NR^(5B)R^(5C),—N(O)_(m1), —NR^(5B)R^(5C), —C(O)R^(5D), —C(O)OR^(5D),—C(O)NR^(5B)R^(5C), —OR^(5A), —NR^(5B)SO₂R^(5A), —NR^(5B)C(O)R^(5D),—NR^(5B)C(O)OR^(5D), —NR^(5B)OR^(5D), —OCX^(5.1) ₃, —OCHX^(5.1) ₂,substituted or unsubstituted alkyl, substituted or unsubstitutedheteroalkyl, substituted or unsubstituted cycloalkyl, substituted orunsubstituted heterocycloalkyl, substituted or unsubstituted aryl, orsubstituted or unsubstituted heteroaryl; R^(1A), R^(1B), R^(1C), R^(1D),R^(2A), R^(2B), R^(2C), R^(2D), R^(3A), R^(3B), R^(3C), R^(3D), R^(4A),R^(4B), R^(4C), R^(4D), R^(5A), R^(5B), R^(5C) and R^(5D) areindependently hydrogen, halogen, —CF₃, —CCl₃, —CBr₃, —CI₃, —OH, —NH₂,—COOH, —CONH₂, —NO₂, —SH, —SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂, —ONH₂,—NHC(O)NHNH₂, —NHC(O)NH₂, —NHSO₂H, —NHC(O)H, —NHC(O)—OH, —NHOH, —OCF₃,—OCCl₃, —OCBr₃, —OCI₃, —OCHF₂, —OCHCl₂, —OCHBr₂, —OCHI₂, substituted orunsubstituted alkyl, substituted or unsubstituted heteroalkyl,substituted or unsubstituted cycloalkyl, substituted or unsubstitutedheterocycloalkyl, substituted or unsubstituted aryl, or substituted orunsubstituted heteroaryl; R^(1B), R^(1C), R^(2B), R^(2C), R^(3B),R^(3C), R^(4B), R^(4C), R^(5B) and R^(5C) substituents bonded to thesame nitrogen atom may optionally be joined to form a substituted orunsubstituted heterocycloalkyl or substituted or unsubstitutedheteroaryl; and X^(1.1), X^(2.1), X^(3.1), X^(4.1) and X^(5.1) areindependently —Cl, —Br, —I or —F.

Embodiment P13

The method of embodiment P12, further comprising administering to thesubject an anti-constipation agent.

Embodiment P14

The method of embodiment P12, wherein the compound is administeredorally.

Embodiment P15

The method of embodiment P12, wherein the constipation is opioid-inducedconstipation, chronic idiopathic constipation or irritable bowelsyndrome with constipation predominance.

Embodiment P16

A method of treating a dry eye disorder, comprising administering to asubject in need thereof a therapeutically effective amount of a compoundof structural Formula (I):

or a pharmaceutically acceptable salt thereof, wherein: Ar issubstituted or unsubstituted aryl or substituted or unsubstitutedheteroaryl; L¹ and L² are independently substituted or unsubstitutedC₁-C₃ alkylene; n1 is an integer from 0 to 4; m1 and v1 areindependently 1 or 2; R¹ is hydrogen, halogen, —CX^(1.1) ₃, —CHX^(1.1)₂, —CH₂X^(1.1), —CN, —SO_(n1)R^(1A), —SO_(v1)NR^(1B)R^(1C),—NHNR^(1B)R^(1C), —ONR^(1B)R^(1C), —NHC(O)NHNR^(1B)R^(1C),—NHC(O)NR^(1B)R^(1C), —N(O)_(m1), —NR^(1B)R^(1C), —C(O)R^(1D),—C(O)OR^(1D), —C(O)NR^(1B)R^(1C), —OR^(1A), —NR^(1B)SO₂R^(1A),—NR^(1B)C(O)R^(1D), —NR^(1B)C(O)OR^(1D), —NR^(1B)OR^(1D), —OCX^(1.1) ₃,—OCHX^(1.1) ₂, substituted or unsubstituted alkyl, substituted orunsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl,substituted or unsubstituted heterocycloalkyl, substituted orunsubstituted aryl, or substituted or unsubstituted heteroaryl; R² ishydrogen, halogen, —CX^(2.1) ₃, —CHX^(2.1) ₂, —CH₂X^(2.1), —CN,—SO_(n1)R^(2A), —SO_(v1)NR^(2B)R^(2C), —NHNR^(2B)R^(2C), —ONR^(2C),—NHC(O)NHNR^(2B)R^(2C), —NHC(O)NR^(2B)R^(2C), —N(O)_(m1),—NR^(2B)R^(2C), —C(O)R^(2D), —C(O)OR^(2D), —C(O)NR^(2B)R^(2C), —OR^(2A),—NR^(2B)SO₂R^(2A), —NR^(2B)C(O)R^(2D), —NR^(2B)C(O)OR^(2D),—NR^(2B)OR^(2D), —OCX^(2.1) ₃, —OCHX^(2.1) ₂, substituted orunsubstituted alkyl, substituted or unsubstituted heteroalkyl,substituted or unsubstituted cycloalkyl, substituted or unsubstitutedheterocycloalkyl, substituted or unsubstituted aryl, or substituted orunsubstituted heteroaryl; R³ is hydrogen, halogen, —CX^(3.1) ₃,—CHX^(3.1) ₂, —CH₂X^(3.1), —CN, —SO_(n1)R^(3A), —SO_(v1)NR^(3B)R^(3C),—NHNR^(3B)R^(3C), —ONR^(3C), —NHC(O)NHNR^(3B)R^(3C),—NHC(O)NR^(3B)R^(3C), —N(O)_(m1), —NR^(3B)R^(3C), —C(O)R^(3D),—C(O)OR^(3D), —C(O)NR^(3B)R^(3C), —OR^(3A), —NR^(3B)SO₂R^(3A),—NR^(3B)C(O)R^(3D), —NR^(3B)C(O)OR^(3D), —NR^(3B)OR^(3D), —OCX^(3.1) ₃,—OCHX^(3.1) ₂, substituted or unsubstituted alkyl, substituted orunsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl,substituted or unsubstituted heterocycloalkyl, substituted orunsubstituted aryl, or substituted or unsubstituted heteroaryl; R⁴ ishydrogen, halogen, —CX^(4.1) ₃, —CHX^(4.1) ₂, —CH₂X^(4.1), —CN,—SO_(n1)R^(4A), —SO_(v1)NR^(4B)R^(4C), —NHNR^(4B)R^(4C), —ONR^(4C),—NHC(O)NHNR^(4B)R^(4C), —NHC(O)NR^(4B)R^(4C), —N(O)_(m1),—NR^(4B)R^(4C), —C(O)R^(4D), —C(O)OR^(4D), —C(O)NR^(4B)R^(4C), —OR^(4A),—NR^(4B)SO₂R^(4A), —NR^(4B)C(O)R^(4D), —NR^(4B)C(O)OR^(4D),—NR^(4B)OR^(4D), —OCX^(4.1) ₃, —OCHX^(4.1) ₂, substituted orunsubstituted alkyl, substituted or unsubstituted heteroalkyl,substituted or unsubstituted cycloalkyl, substituted or unsubstitutedheterocycloalkyl, substituted or unsubstituted aryl, or substituted orunsubstituted heteroaryl; R⁵ is hydrogen, halogen, —CX^(5.1) ₃,—CHX^(5.1) ₂, —CH₂X^(5.1), —CN, —SO_(n1)R^(5A), —SO_(v1)NR^(5B)R^(5C),—NHNR^(5B)R^(5C), —ONR^(5B)R^(5C), —NHC(O)NHNR^(5B)R^(5C),—NHC(O)NR^(5B)R^(5C), —N(O)_(m1), —NR^(5B)R^(5C), —C(O)R^(5D),—C(O)OR^(5D), —C(O)NR^(5B)R^(5C), —OR^(5A), —NR^(5B)SO₂R^(5A),—NR^(5B)C(O)R^(5D), —NR^(5B)C(O)OR^(5D), —NR^(5B)OR^(5D), —OCX^(5.1) ₃,—OCHX^(5.1) ₂, substituted or unsubstituted alkyl, substituted orunsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl,substituted or unsubstituted heterocycloalkyl, substituted orunsubstituted aryl, or substituted or unsubstituted heteroaryl; R^(1A),R^(1B), R^(1C), R^(1D), R^(2A), R^(2B), R^(2C), R^(2D), R^(3A), R^(3B),R^(3C), R^(3D), R^(4A), R^(4B), R^(4C), R^(4D), R^(5A), R^(5B), R^(5C)and R^(5D) are independently hydrogen, halogen, —CF₃, —CCl₃, —CBr₃,—CI₃, —OH, —NH₂, —COOH, —CONH₂, —NO₂, —SH, —SO₃H, —SO₄H, —SO₂NH₂,—NHNH₂, —ONH₂, —NHC(O)NHNH₂, —NHC(O)NH₂, —NHSO₂H, —NHC(O)H, —NHC(O)—OH,—NHOH, —OCF₃, —OCCl₃, —OCBr₃, —OCI₃, —OCHF₂, —OCHCl₂, —OCHBr₂, —OCHI₂,substituted or unsubstituted alkyl, substituted or unsubstitutedheteroalkyl, substituted or unsubstituted cycloalkyl, substituted orunsubstituted heterocycloalkyl, substituted or unsubstituted aryl, orsubstituted or unsubstituted heteroaryl; R^(1B), R^(1C), R^(2B), R^(2C),R^(3B), R^(3C), R^(4B), R^(4C), R^(5B) and R^(5C) substituents bonded tothe same nitrogen atom may optionally be joined to form a substituted orunsubstituted heterocycloalkyl or substituted or unsubstitutedheteroaryl; and X^(1.1), X^(2.1), X^(3.1), X^(4.1) and X^(5.1) areindependently —Cl, —Br, —I or —F.

Embodiment P17

The method of embodiment P16, wherein the dry eye disorder is a lacrimalgland disorder.

Embodiment P18

The method of embodiment P16, further comprising administering to thesubject an anti-dry eye agent.

Embodiment P19

A method of increasing lacrimation, comprising administering to asubject in need thereof a compound of structural Formula (I):

or a pharmaceutically acceptable salt thereof, wherein: Ar issubstituted or unsubstituted aryl or substituted or unsubstitutedheteroaryl; L¹ and L² are independently substituted or unsubstitutedC₁-C₃ alkylene; n1 is an integer from 0 to 4; m1 and v1 areindependently 1 or 2; R¹ is hydrogen, halogen, —CX^(1.1) ₃, —CHX^(1.1)₂, —CH₂X^(1.1), —CN, —SO_(n1)R^(1A), —SO_(v1)NR^(1B)R^(1C),—NHNR^(1B)R^(1C), —ONR^(1B)R^(1C), —NHC(O)NHNR^(1B)R^(1C),—NHC(O)NR^(1B)R^(1C), —N(O)_(m1), —NR^(1B)R^(1C), —C(O)R^(1D),—C(O)OR^(1D), —C(O)NR^(1B)R^(1C), —OR^(1A), —NR^(1B)SO₂R^(1A),—NR^(1B)C(O)R^(1D), —NR^(1B)C(O)OR^(1D)_NR^(1B)OR^(1D), —OCX^(1.1) ₃,—OCHX^(1.1) ₂, substituted or unsubstituted alkyl, substituted orunsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl,substituted or unsubstituted heterocycloalkyl, substituted orunsubstituted aryl, or substituted or unsubstituted heteroaryl; R² ishydrogen, halogen, —CX^(2.1) ₃, —CHX^(2.1) ₂, —CH₂X^(2.1), —CN,—SO_(n1)R^(2A), —SO_(v1)NR^(2B)R^(2C), —NHNR^(2B)R^(2C),—ONR^(2B)R^(2C), —NHC(O)NHNR^(2B)R^(2C), —NHC(O)NR^(2B)R^(2C),—N(O)_(m1), —NR^(2B)R^(2C), —C(O)R^(2D), —C(O)OR^(2D),—C(O)NR^(2B)R^(2C), —OR^(2A), —NR^(2B)SO₂R^(2A), —NR^(2B)C(O)R^(2D),—NR^(2B)C(O)OR^(2D), —NR^(2B)OR^(2D), —OCX^(2.1) ₃, —OCHX^(2.1) ₂,substituted or unsubstituted alkyl, substituted or unsubstitutedheteroalkyl, substituted or unsubstituted cycloalkyl, substituted orunsubstituted heterocycloalkyl, substituted or unsubstituted aryl, orsubstituted or unsubstituted heteroaryl; R³ is hydrogen, halogen,—CX^(3.1) ₃, —CHX^(3.1) ₂, —CH₂X^(3.1), —CN, —SO_(n1)R^(3A),—SO_(v1)NR^(3B)R^(3C), —NHNR^(3B)R^(3C), —ONR^(3B)R^(3C),—NHC(O)NHNR^(3B)R^(3C), —NHC(O)NR^(3B)R^(3C), —N(O)_(m1),—NR^(3B)R^(3C), —C(O)R^(3D), —C(O)OR^(3D), —C(O)NR^(3B)R^(3C), —OR^(3A),—NR^(3B)SO₂R^(3A), —NR^(3B)C(O)R^(3D), —NR^(3B)C(O)OR^(3D),—NR^(3B)OR^(3D), —OCX^(3.1) ₃, —OCHX^(3.1) ₂, substituted orunsubstituted alkyl, substituted or unsubstituted heteroalkyl,substituted or unsubstituted cycloalkyl, substituted or unsubstitutedheterocycloalkyl, substituted or unsubstituted aryl, or substituted orunsubstituted heteroaryl; R⁴ is hydrogen, halogen, —CX^(4.1) ₃,—CHX^(4.1) ₂, —CH₂X^(4.1), —CN, —SO_(n1)R^(4A), —SO_(v1)NR^(4B)R^(4C),—NHNR^(4B)R^(4C), —ONR^(4B)R^(4C), —NHC(O)NHNR^(4B)R^(4C),—NHC(O)NR^(4B)R^(4C), —N(O)_(m1), —NR^(4B)R^(4C), —C(O)R^(4D),—C(O)OR^(4D), —C(O)NR^(4B)R^(4C), —OR^(4A), —NR^(4B)SO₂R^(4A),—NR^(4B)C(O)R^(4D), —NR^(4B)C(O)OR^(4D), —NR^(4B)OR^(4D), —OCX^(4.1) ₃,—OCHX^(4.1) ₂, substituted or unsubstituted alkyl, substituted orunsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl,substituted or unsubstituted heterocycloalkyl, substituted orunsubstituted aryl, or substituted or unsubstituted heteroaryl; R⁵ ishydrogen, halogen, —CX^(5.1) ₃, —CHX^(5.1) ₂, —CH₂X^(5.1), —CN,—SO_(n1)R^(5A), —SO_(v1)NR^(5B)R^(5C), —NHNR^(5B)R^(5C),—ONR^(5B)R^(5C), —NHC(O)NHNR^(5B)R^(5C), —NHC(O)NR^(5B)R^(5C),—N(O)_(m1), —NR^(5B)R^(5C), —C(O)R^(5D), —C(O)OR^(5D),—C(O)NR^(5B)R^(5C), —OR^(5A), —NR^(5B)SO₂R^(5A), —NR^(5B)C(O)R^(5D),—NR^(5B)C(O)OR^(5D), —NR^(5B)OR^(5D), —OCX^(5.1) ₃, —OCHX^(5.1) ₂,substituted or unsubstituted alkyl, substituted or unsubstitutedheteroalkyl, substituted or unsubstituted cycloalkyl, substituted orunsubstituted heterocycloalkyl, substituted or unsubstituted aryl, orsubstituted or unsubstituted heteroaryl; R^(1A), R^(1B), R^(1C), R^(1D),R^(2A), R^(2B), R^(2C), R^(2D), R^(3A), R^(3B), R^(3C), R^(3D), R^(4A),R^(4B), R^(4C), R^(4D), R^(5A), R^(5B), R^(5C) and R^(5D) areindependently hydrogen, halogen, —CF₃, —CCl₃, —CBr₃, —CI₃, —OH, —NH₂,—COOH, —CONH₂, —NO₂, —SH, —SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂, —ONH₂,—NHC(O)NHNH₂, —NHC(O)NH₂, —NHSO₂H, —NHC(O)H, —NHC(O)—OH, —NHOH, —OCF₃,—OCCl₃, —OCBr₃, —OCI₃, —OCHF₂, —OCHCl₂, —OCHBr₂, —OCHI₂, substituted orunsubstituted alkyl, substituted or unsubstituted heteroalkyl,substituted or unsubstituted cycloalkyl, substituted or unsubstitutedheterocycloalkyl, substituted or unsubstituted aryl, or substituted orunsubstituted heteroaryl; R^(1B), R^(1C), R^(2B), R^(2C), R^(3B),R^(3C), R^(4B), R^(4C), R^(5B) and R^(5C) substituents bonded to thesame nitrogen atom may optionally be joined to form a substituted orunsubstituted heterocycloalkyl or substituted or unsubstitutedheteroaryl; and X^(1.1), X^(2.1), X^(3.1), X^(4.1) and X^(5.1) areindependently —Cl, —Br, —I or —F.

Embodiment P20

A method of activating Cystic Fibrosis Transmembrane ConductanceRegulator (CFTR), comprising contacting CFTR with a compound ofstructural Formula (I):

or a pharmaceutically acceptable salt thereof, wherein: Ar issubstituted or unsubstituted aryl or substituted or unsubstitutedheteroaryl; L¹ and L² are independently substituted or unsubstitutedC₁-C₃ alkylene; n1 is an integer from 0 to 4; m1 and v1 areindependently 1 or 2; R¹ is hydrogen, halogen, —CX^(1.1) ₃, —CHX^(1.1)₂, —CH₂X^(1.1), —CN, —SO_(n1)R^(1A), —SO_(v1)NR^(1B)R^(1C),—NHNR^(1B)R^(1C), —ONR^(1B)R^(1C), —NHC(O)NHNR^(1B)R^(1C),—NHC(O)NR^(1B)R^(1C), —N(O)_(m1), —NR^(1B)R^(1C), —C(O)R^(1D),—C(O)OR^(1D), —C(O)NR^(1B)R^(1C), —OR^(1A), —NR^(1B)SO₂R^(1A),—NR^(1B)C(O)R^(1D), —NR^(1B)C(O)OR^(1D), —NR^(1B)OR^(1D), —OCX^(1.1) ₃,—OCHX^(1.1) ₂, substituted or unsubstituted alkyl, substituted orunsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl,substituted or unsubstituted heterocycloalkyl, substituted orunsubstituted aryl, or substituted or unsubstituted heteroaryl; R² ishydrogen, halogen, —CX^(2.1) ₃, —CHX^(2.1) ₂, —CH₂X^(2.1), —CN,—SO_(n1)R^(2A), —SO_(v1)NR^(2B)R^(2C), —NHNR^(2B)R^(2C),—ONR^(2B)R^(2C), —NHC(O)NHNR^(2B)R^(2C), —NHC(O)NR^(2B)R^(2C),—N(O)_(m1), —NR^(2B)R^(2C), —C(O)R^(2D), —C(O)OR^(2D),—C(O)NR^(2B)R^(2C), —OR^(2A), —NR^(2B)SO₂R^(2A), —NR^(2B)C(O)R^(2D),—NR^(2B)C(O)OR^(2D), —NR^(2B)OR^(2D), —OCX^(2.1) ₃, —OCHX^(2.1) ₂,substituted or unsubstituted alkyl, substituted or unsubstitutedheteroalkyl, substituted or unsubstituted cycloalkyl, substituted orunsubstituted heterocycloalkyl, substituted or unsubstituted aryl, orsubstituted or unsubstituted heteroaryl; R³ is hydrogen, halogen,—CX^(3.1) ₃, —CHX^(3.1) ₂, —CH₂X^(3.1), —CN, —SO_(n1)R^(3A),—SO_(v1)NR^(3B)R^(3C), —NHNR^(3B)R^(3C), —ONR^(3B)R^(3C),—NHC(O)NHNR^(3B)R^(3C), —NHC(O)NR^(3B)R^(3C), —N(O)_(m1),—NR^(3B)R^(3C), —C(O)R^(3D), —C(O)OR^(3D), —C(O)NR^(3B)R^(3C), —OR^(3A),—NR^(3B)SO₂R^(3A), —NR^(3B)C(O)R^(3D), —NR^(3B)C(O)OR^(3D),—NR^(3B)OR^(3D), —OCX^(3.1) ₃, —OCHX^(3.1) ₂, substituted orunsubstituted alkyl, substituted or unsubstituted heteroalkyl,substituted or unsubstituted cycloalkyl, substituted or unsubstitutedheterocycloalkyl, substituted or unsubstituted aryl, or substituted orunsubstituted heteroaryl; R⁴ is hydrogen, halogen, —CX^(4.1) ₃,—CHX^(4.1) ₂, —CH₂X^(4.1), —CN, —SO_(n1)R^(4A), —SO_(v1)NR^(4B)R^(4C),—NHNR^(4B)R^(4C), —ONR^(4B)R^(4C), —NHC(O)NHNR^(4B)R^(4C),—NHC(O)NR^(4B)R^(4C), —N(O)_(m1), —NR^(4B)R^(4C), —C(O)R^(4D),—C(O)OR^(4D), —C(O)NR^(4B)R^(4C), —OR^(4A), —NR^(4B)SO₂R^(4A),—NR^(4B)C(O)R^(4D), —NR^(4B)C(O)OR^(4D), —NR^(4B)OR^(4D), —OCX^(4.1) ₃,—OCHX^(4.1) ₂, substituted or unsubstituted alkyl, substituted orunsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl,substituted or unsubstituted heterocycloalkyl, substituted orunsubstituted aryl, or substituted or unsubstituted heteroaryl; R⁵ ishydrogen, halogen, —CX^(5.1) ₃, —CHX^(5.1) ₂, —CH₂X^(5.1), —CN,—SO_(n1)R^(5A), —SO_(v1)NR^(5B)R^(5C), —NHNR^(5B)R^(5C),—ONR^(5B)R^(5C), —NHC(O)NHNR^(5B)R^(5C), —NHC(O)NR^(5B)R^(5C),—N(O)_(m1), —NR^(5B)R^(5C), —C(O)R^(5D), —C(O)OR^(5D),—C(O)NR^(5B)R^(5C), —OR^(5A), —NR^(5B)SO₂R^(5A), —NR^(5B)C(O)R^(5D),—NR^(5B)C(O)OR^(5D), —NR^(5B)OR^(5D), —OCX^(5.1) ₃, —OCHX^(5.1) ₂,substituted or unsubstituted alkyl, substituted or unsubstitutedheteroalkyl, substituted or unsubstituted cycloalkyl, substituted orunsubstituted heterocycloalkyl, substituted or unsubstituted aryl, orsubstituted or unsubstituted heteroaryl; R^(1A), R^(1B), R^(1C), R^(1D),R^(2A), R^(2B), R^(2C), R^(2D), R^(3A), R^(3B), R^(3C), R^(3D), R^(4A),R^(4B), R^(4C), R^(4D), R^(5A), R^(5B), R^(5C) and R^(5D) areindependently hydrogen, halogen, —CF₃, —CCl₃, —CBr₃, —CI₃, —OH, —NH₂,—COOH, —CONH₂, —NO₂, —SH, —SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂, —ONH₂,—NHC(O)NHNH₂, —NHC(O)NH₂, —NHSO₂H, —NHC(O)H, —NHC(O)—OH, —NHOH, —OCF₃,—OCCl₃, —OCBr₃, —OCI₃, —OCHF₂, —OCHCl₂, —OCHBr₂, —OCHI₂, substituted orunsubstituted alkyl, substituted or unsubstituted heteroalkyl,substituted or unsubstituted cycloalkyl, substituted or unsubstitutedheterocycloalkyl, substituted or unsubstituted aryl, or substituted orunsubstituted heteroaryl; R^(1B), R^(1C), R^(2B), R^(2C), R^(3B),R^(3C), R^(4B), R^(4C), R^(5B) and R^(5C) substituents bonded to thesame nitrogen atom may optionally be joined to form a substituted orunsubstituted heterocycloalkyl or substituted or unsubstitutedheteroaryl; and X^(1.1), X^(2.1), X^(3.1), X^(4.1) and X^(5.1) areindependently —Cl, —Br, —I or —F.

Further embodiments contemplated herein include embodiments 1 to 48following.

Embodiment 1

A pharmaceutical composition, comprising a pharmaceutically acceptableexcipient, and a compound of Formula I:

or a pharmaceutically acceptable salt thereof, wherein: Ar issubstituted or unsubstituted aryl or substituted or unsubstitutedheteroaryl; L¹ and L² are independently substituted or unsubstitutedC₁-C₃ alkylene; n1, n2, n3, n4 and n5 are independently an integer from0 to 4; m1, m2, m3, m4, m5, v1, v2, v3, v4 and v5 are independently 1 or2; R¹ is hydrogen, halogen, —CX^(1.1) ₃, —CHX^(1.1) ₂, —CH₂X^(1.1), —CN,—SO_(n1)R^(1A), —SO_(v1)NR^(1B)R^(1C), —NHNR^(1B)R^(1C),—ONR^(1B)R^(1C), —NHC(O)NHNR^(1B)R^(1C), —NHC(O)NR^(1B)R^(1C),—N(O)_(m1), —NR^(1B)R^(1C), —C(O)R^(1D), —C(O)OR^(1D),—C(O)NR^(1B)R^(1C), —OR^(1A), —NR^(1B)SO₂R^(1A), —NR^(1B)C(O)R^(1D),—NR^(1B)C(O)OR^(1D), —NR^(1B)OR^(1D), —OCX^(1.1) ₃, —OCHX^(1.1) ₂,substituted or unsubstituted alkyl, substituted or unsubstitutedheteroalkyl, substituted or unsubstituted cycloalkyl, substituted orunsubstituted heterocycloalkyl, substituted or unsubstituted aryl, orsubstituted or unsubstituted heteroaryl; R² is hydrogen, halogen,—CX^(2.1) ₃, —CHX^(2.1) ₂, —CH₂X^(2.1), —CN, —SO_(n2)R^(2A),—SO₂NR^(2B)R^(2C), —NHNR^(2B)R^(2C), —ONR^(2B)R²,—NHC(O)NHNR^(2B)R^(2C), —NHC(O)NR^(2B)R^(2C), —N(O)_(m2),—NR^(2B)R^(2C), —C(O)R^(2D), —C(O)OR^(2D), —C(O)NR^(2B)R^(2C), —OR^(2A),—NR^(2B)SO₂R^(2A), —NR^(2B)C(O)R^(2D), —NR^(2B)C(O)OR^(2D),—NR^(2B)OR^(2D), —OCX^(2.1) ₃, —OCHX^(2.1) ₂, substituted orunsubstituted alkyl, substituted or unsubstituted heteroalkyl,substituted or unsubstituted cycloalkyl, substituted or unsubstitutedheterocycloalkyl, substituted or unsubstituted aryl, or substituted orunsubstituted heteroaryl; R³ is hydrogen, halogen, —CX^(3.1) ₃,—CHX^(3.1) ₂, —CH₂X^(3.1), —CN, —SO_(n3)R^(3A), —SO_(v3)NR^(3B)R^(3C),—NHNR^(3B)R^(3C), —ONR^(3B)R^(3C), —NHC(O)NHNR^(3B)R^(3C),—NHC(O)NR^(3B)R^(3C), —N(O)_(m3), —NR^(3B)R^(3C), —C(O)R^(3D),—C(O)OR^(3D), —C(O)NR^(3B)R^(3C), —OR^(3A), —NR^(3B)SO₂R^(3A),—NR^(3B)C(O)R^(3D), —NR^(3B)C(O)OR^(3D), —NR^(3B)OR^(3D), —OCX^(3.1) ₃,—OCHX^(3.1) ₂, substituted or unsubstituted alkyl, substituted orunsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl,substituted or unsubstituted heterocycloalkyl, substituted orunsubstituted aryl, or substituted or unsubstituted heteroaryl; R⁴ ishydrogen, halogen, —CX^(4.1) ₃, —CHX^(4.1) ₂, —CH₂X^(4.1), —CN,—SO_(n4)R^(4A), —SO_(v4)NR^(4B)R^(4C), —NHNR^(4B)R^(4C),—ONR^(4B)R^(4C), —NHC(O)NHNR^(4B)R^(4C), —NHC(O)NR^(4B)R^(4C),—N(O)_(m4), —NR^(4B)R^(4C), —C(O)R^(4D), —C(O)OR^(4D),—C(O)NR^(4B)R^(4C), —OR^(4A), —NR^(4B)SO₂R^(4A), —NR^(4B)C(O)R^(4D),—NR^(4B)C(O)OR^(4D), —NR^(4B)OR^(4D), —OCX^(4.1) ₃, —OCHX^(4.1) ₂,substituted or unsubstituted alkyl, substituted or unsubstitutedheteroalkyl, substituted or unsubstituted cycloalkyl, substituted orunsubstituted heterocycloalkyl, substituted or unsubstituted aryl, orsubstituted or unsubstituted heteroaryl; R⁵ is hydrogen, halogen,—CX^(5.1) ₃, —CHX^(5.1) ₂, —CH₂X^(5.1), —CN, —SO_(n1)R^(5A),—SO_(v5)NR^(5B)R^(5C), —NHNR^(5B)R^(5C), —ONR^(5B)R^(5C),—NHC(O)NHNR^(5B)R^(5C), —NHC(O)NR^(5B)R^(5C), —N(O)_(m5),—NR^(5B)R^(5C), —C(O)R^(5D), —C(O)OR^(5D), —C(O)NR^(5B)R^(5C), —OR^(5A),—NR^(5B)SO₂R^(5A), —NR^(5B)C(O)R^(5D), —NR^(5B)C(O)OR^(5D),—NR^(5B)OR^(5D), —OCX^(5.1) ₃, —OCHX^(5.1) ₂, substituted orunsubstituted alkyl, substituted or unsubstituted heteroalkyl,substituted or unsubstituted cycloalkyl, substituted or unsubstitutedheterocycloalkyl, substituted or unsubstituted aryl, or substituted orunsubstituted heteroaryl; R^(1A), R^(1B), R^(1C), R^(1D), R^(2A),R^(2B), R^(2C), R^(2D), R^(3A), R^(3B), R^(3C), R^(3D), R^(4A), R^(4B),R^(4C), R^(4D), R^(5A), R^(5B), R^(5C) and R^(5D) are independentlyhydrogen, halogen, —CF₃, —CCl₃, —CBr₃, —CI₃, —OH, —NH₂, —COOH, —CONH₂,—NO₂, —SH, —SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂, —ONH₂, —NHC(O)NHNH₂,—NHC(O)NH₂, —NHSO₂H, —NHC(O)H, —NHC(O)—OH, —NHOH, —OCF₃, —OCCl₃, —OCBr₃,—OCI₃, —OCHF₂, —OCHCl₂, —OCHBr₂, —OCHI₂, substituted or unsubstitutedalkyl, substituted or unsubstituted heteroalkyl, substituted orunsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl,substituted or unsubstituted aryl, or substituted or unsubstitutedheteroaryl; R^(1B), R^(1C), R^(2B), R^(2C), R^(3B), R^(3C), R^(4B),R^(4C), R^(5B) and R^(5C) substituents bonded to the same nitrogen atommay optionally be joined to form a substituted or unsubstitutedheterocycloalkyl or substituted or unsubstituted heteroaryl; andX^(1.1), X^(2.1), X^(3.1), X^(4.1) and X^(5.1) are independently —Cl,—Br, —I or —F.

Embodiment 2

The pharmaceutical composition of embodiment 1, wherein: Ar isunsubstituted heteroaryl; L¹ and L² are —CH₂—; and R¹, R², R³, R⁴ and R⁵are independently hydrogen, —OCH₃ or —OCH₂CH₃.

Embodiment 3

The pharmaceutical composition of embodiment 2, wherein R¹, R⁴ and R⁵are hydrogen.

Embodiment 4

The pharmaceutical composition of embodiment 2 or 3, wherein R² and R³are —OCH₃.

Embodiment 5

The pharmaceutical composition of embodiment 2, 3 or 4, wherein Ar isunsubstituted 2-thienyl.

Embodiment 6

The pharmaceutical composition of embodiment 1, 2, 3, 4 or 5, whereinthe compound is

Embodiment 7

A pharmaceutical composition, comprising a pharmaceutically acceptableexcipient, and a compound of Formula IA:

or a pharmaceutically acceptable salt thereof, wherein: Ar issubstituted or unsubstituted aryl or substituted or unsubstitutedheteroaryl; L¹ and L² are independently substituted or unsubstitutedC₁-C₃ alkylene; n1, n2, n3, n4, n5, n6, n7, n8, n9 and n10 areindependently an integer from 0 to 4; m1, m2, m3, m4, m5, m6, m7, m8,m9, m10, v1, v2, v3, v4, v5, v6, v7, v8, v9 and v10 are independently 1or 2; R¹ is hydrogen, halogen, —CX^(1.1) ₃, —CHX^(1.1) ₂, —CH₂X^(1.1),—CN, —SO_(n1)R^(1A), —SO_(v1)NR^(1B)R^(1C), —NHNR^(1B)R^(1C),—ONR^(1B)R^(1C), —NHC(O)NHNR^(1B)R^(1C), —NHC(O)NR^(1B)R^(1C),—N(O)_(m1), —NR^(1B)R^(1C), —C(O)R^(1D), —C(O)OR^(1D),—C(O)NR^(1B)R^(1C), —OR^(1A), —NR^(1B)SO₂R^(1A), —NR^(1B)C(O)R^(1D),—NR^(1B)C(O)OR^(1D), —NR^(1B)OR^(1D), —OCX^(1.1) ₃, —OCHX^(1.1) ₂,substituted or unsubstituted alkyl, substituted or unsubstitutedheteroalkyl, substituted or unsubstituted cycloalkyl, substituted orunsubstituted heterocycloalkyl, substituted or unsubstituted aryl, orsubstituted or unsubstituted heteroaryl; R² is hydrogen, halogen,—CX^(2.1) ₃, —CHX^(2.1) ₂, —CH₂X^(2.1), —CN, —SO_(n2)R^(2A),—SO_(v2)NR^(2B)R^(2C), —NHNR^(2B)R^(2C), —ONR^(2B)R^(2C),—NHC(O)NHNR^(2B)R^(2C), —NHC(O)NR^(2B)R^(2C), —N(O)_(m2),—NR^(2B)R^(2C), —C(O)R^(2D), —C(O)OR^(2D), —C(O)NR^(2B)R^(2C), —OR^(2A),—NR^(2B)SO₂R^(2A), —NR^(2B)C(O)R^(2D), —NR^(2B)C(O)OR^(2D),—NR^(2B)OR^(2D), —OCX^(2.1) ₃, —OCHX^(2.1) ₂, substituted orunsubstituted alkyl, substituted or unsubstituted heteroalkyl,substituted or unsubstituted cycloalkyl, substituted or unsubstitutedheterocycloalkyl, substituted or unsubstituted aryl, or substituted orunsubstituted heteroaryl; R³ is hydrogen, —CX^(3.1) ₃, —CHX^(3.1) ₂,—CH₂X^(3.1), —CN, —SO_(n3)R^(3A), —SO_(v3)NR^(3B)R^(3C),—NHNR^(3B)R^(3C), —ONR^(3B)R^(3C), —NHC(O)NHNR^(3B)R^(3C),—NHC(O)NR^(3B)R^(3C), —N(O)_(m3), —NR^(3B)R^(3C), —C(O)R^(3D),—C(O)OR^(3D), —C(O)NR^(3B)R^(3C), —OR^(3A), —NR^(3B)SO₂R^(3A),—NR^(3B)C(O)R^(3D), —NR^(3B)C(O)OR^(3D), —NR^(3B)OR^(3D), —OCX^(3.1) ₃,—OCHX^(3.1) ₂, substituted or unsubstituted alkyl, substituted orunsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl,substituted or unsubstituted heterocycloalkyl, substituted orunsubstituted aryl, or substituted or unsubstituted heteroaryl; R⁴ ishydrogen, halogen, —CX^(4.1) ₃, —CHX^(4.1) ₂, —CH₂X^(4.1), —CN,—SO_(n4)R^(4A), —SO_(v4)NR^(4B)R^(4C), —NHNR^(4B)R^(4C),—ONR^(4B)R^(4C), —NHC(O)NHNR^(4B)R^(4C), —NHC(O)NR^(4B)R^(4C),—N(O)_(m4), —NR^(4B)R^(4C), —C(O)R^(4D), —C(O)OR^(4D),—C(O)NR^(4B)R^(4C), —OR^(4A), —NR^(4B)SO₂R^(4A), —NR^(4B)C(O)R^(4D),—NR^(4B)C(O)OR^(4D), —NR^(4B)OR^(4D), —OCX^(4.1) ₃, —OCHX^(4.1) ₂,substituted or unsubstituted alkyl, substituted or unsubstitutedheteroalkyl, substituted or unsubstituted cycloalkyl, substituted orunsubstituted heterocycloalkyl, substituted or unsubstituted aryl, orsubstituted or unsubstituted heteroaryl; R⁵ is hydrogen, halogen,—CX^(5.1) ₃, —CHX^(5.1) ₂, —CH₂X^(5.1), —CN, —SO_(n1)R^(5A),—SO_(v5)NR^(5B)R^(5C), —NHNR^(5B)R^(5C), —ONR^(5B)R^(5C),—NHC(O)NHNR^(5B)R^(5C), —NHC(O)NR^(5B)R^(5C), —N(O)_(m5),—NR^(5B)R^(5C), —C(O)R^(5D), —C(O)OR^(5D), —C(O)NR^(5B)R^(5C), —OR^(5A),—NR^(5B)SO₂R^(5A), —NR^(5B)C(O)R^(5D), —NR^(1B)C(O)OR^(5D),—NR^(5B)OR^(5D), —OCX^(5.1) ₃, —OCHX^(5.1) ₂, substituted orunsubstituted alkyl, substituted or unsubstituted heteroalkyl,substituted or unsubstituted cycloalkyl, substituted or unsubstitutedheterocycloalkyl, substituted or unsubstituted aryl, or substituted orunsubstituted heteroaryl; R⁶ is hydrogen, halogen, —CX^(6.1) ₃,—CHX^(6.1) ₂, —CH₂X^(6.1), —CN, —SO_(n6)R^(6A), SO_(v6)NR^(6B)R^(6C),—NHNR^(6B)R^(6C), —ONR^(6B)R^(6C), —NHC(O)NHNR^(6B)R^(6C),—NHC(O)NR^(6B)R^(6C), —N(O)_(m6), —NR^(6B)R^(6C), —C(O)R^(6D),—C(O)OR^(6D), —C(O)NR^(6B)R^(6C), —OR^(6A), —NR^(6B)SO₂R^(6A),—NR^(6B)C(O)R^(6D), —NR^(6B)C(O)OR^(6D), —NR^(6B)OR^(6D), —OCX^(6.1) ₃,—OCHX^(6.1) ₂, substituted or unsubstituted alkyl, substituted orunsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl,substituted or unsubstituted heterocycloalkyl, substituted orunsubstituted aryl, or substituted or unsubstituted heteroaryl; R⁷ ishydrogen, halogen, —CX^(7.1) ₃, —CHX^(7.1) ₂, —CH₂X^(7.1), —CN,—SO_(n1)R^(7A), —SO_(v7)NR^(7B)R^(7C), —NHNR^(7B)R^(7C),—ONR^(7B)R^(7C), —NHC(O)NHNR^(7B)R^(7C), —NHC(O)NR^(7B)R^(7C),—N(O)_(m7), —NR^(7B)R^(7C), —C(O)R^(7D), —C(O)OR^(7D),—C(O)NR^(7B)R^(7C), —OR^(7A), —NR^(7B)SO₂R^(7A), —NR^(7A)C(O)R^(7C),—NR^(7B)C(O)OR^(7D), —NR^(7B)OR^(7D), —OCX^(7.8) ₃, —OCHX^(7.1) ₂,substituted or unsubstituted alkyl, substituted or unsubstitutedheteroalkyl, substituted or unsubstituted cycloalkyl, substituted orunsubstituted heterocycloalkyl, substituted or unsubstituted aryl, orsubstituted or unsubstituted heteroaryl; R⁸ is hydrogen, halogen,—CX^(8.1) ₃, —CHX^(8.1) ₂, —CH₂X^(8.1), —CN, —SO_(n8)R^(8A),—SO_(v1)NR^(8B)R^(8C), —NHNR^(8B)R^(8C), —ONR^(8B)R^(8C),—NHC(O)NHNR^(8B)R^(8C), —NHC(O)NR^(8B)R^(8C), —N(O)_(m8),—NR^(8B)R^(8C), —C(O)R^(8D), —C(O)OR^(8D), —C(O)NR^(8B)R^(8C), —OR^(8A),—NR^(8B)SO₂R^(8A), —NR^(8B)C(O)R^(8D), —NR^(8B)C(O)OR^(8D),—NR^(8B)OR^(8D), —OCX^(8.1) ₃, —OCHX^(8.1) ₂, substituted orunsubstituted alkyl, substituted or unsubstituted heteroalkyl,substituted or unsubstituted cycloalkyl, substituted or unsubstitutedheterocycloalkyl, substituted or unsubstituted aryl, or substituted orunsubstituted heteroaryl; R⁹ is hydrogen, halogen, —CX^(9.1) ₃,—CHX^(9.1) ₂, —CH₂X^(9.1), —CN, —SO_(n9)R^(9A), —SO_(v9)NR^(9B)R^(9C),—NHNR^(9B)R^(9C), —ONR^(9B)R^(9C), —NHC(O)NHNR^(9B)R^(9C),—NHC(O)NR^(9B)R^(9C), —N(O)_(m9), —NR^(9B)R^(9C), —C(O)R^(9D),—C(O)OR^(9D), —C(O)NR^(9B)R^(9C), —OR^(9A), —NR^(9B)SO₂R^(9A),—NR^(9B)C(O)R^(9D), —NR^(9B)C(O)OR^(9D), —NR^(9B)OR^(9D), —OCX^(9.1) ₃,—OCHX^(9.1) ₂, substituted or unsubstituted alkyl, substituted orunsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl,substituted or unsubstituted heterocycloalkyl, substituted orunsubstituted aryl, or substituted or unsubstituted heteroaryl; R¹⁰ ishydrogen, halogen, —CX^(10.1) ₃, —CHX^(10.1) ₂, —CH₂X^(10.1), —CN,—SO_(n10)R^(10A), —SO_(v10)NR^(10B)R^(10C), —NHNR^(10B)R^(10C),—ONR^(10B)R^(10C), —NHC(O)NHNR^(10B)R^(10C), —NHC(O)NR^(10B)R^(10C),—N(O)_(m10), —NR^(10B)R^(10C), —C(O)R^(10D), —C(O)OR^(10D),—C(O)NR^(10B)R^(10C), —OR^(10A), —NR^(10B)SO₂R^(10A),—NR^(10B)C(O)R^(10D), —NR^(10B)C(O)OR^(10D), —NR^(10B)OR^(10D),—OCX^(10.1) ₃, —OCHX^(10.1) ₂, substituted or unsubstituted alkyl,substituted or unsubstituted heteroalkyl, substituted or unsubstitutedcycloalkyl, substituted or unsubstituted heterocycloalkyl, substitutedor unsubstituted aryl, or substituted or unsubstituted heteroaryl;R^(1A), R^(1B), R^(1C), R^(1D), R^(2A), R^(2B), R^(2C), R^(2D), R^(3A),R^(3B), R^(3C), R^(3D), R^(4A), R^(4B), R^(4C), R^(4D), R^(5A), R^(5B),R^(5C), R^(5D), R^(6A), R^(6B), R^(6C), R^(6D), R^(7A), R^(7B), R^(7C),R^(7D), R^(8A), R^(8B), R^(8C), R^(8D), R^(9A), R^(9B), R^(9C), R^(9D),R^(10A), R^(10B), R^(10C) and R^(10D) are independently hydrogen,halogen, —CF₃, —CCl₃, —CBr₃, —CI₃, —OH, —NH₂, —COOH, —CONH₂, —NO₂, —SH,—SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂, —ONH₂, —NHC(O)NHNH₂, —NHC(O)NH₂, —NHSO₂H,—NHC(O)H, —NHC(O)—OH, —NHOH, —OCF₃, —OCCl₃, —OCBr₃, —OCI₃, —OCHF₂,—OCHCl₂, —OCHBr₂, —OCHI₂, substituted or unsubstituted alkyl,substituted or unsubstituted heteroalkyl, substituted or unsubstitutedcycloalkyl, substituted or unsubstituted heterocycloalkyl, substitutedor unsubstituted aryl, or substituted or unsubstituted heteroaryl;R^(1B), R^(1C), R^(2B), R^(2C), R^(3B), R^(3C), R^(4B), R^(4C), R^(5B),R^(5C), R^(6B), R^(6C), R^(7B), R^(7C), R^(8B), R^(8C), R^(9B), R^(9C),R^(10B) and R^(10C) substituents bonded to the same nitrogen atom mayoptionally be joined to form a substituted or unsubstitutedheterocycloalkyl or substituted or unsubstituted heteroaryl; andX^(1.1), X^(2.1), X^(3.1), X^(4.1) X^(5.1), X^(6.1), X^(7.1), X^(8.1),X^(9.1) and X^(10.1) are independently —Cl, —Br, —I or —F, with provisothat when L¹ and L² are independently unsubstituted C₁-C₃ alkylene, R²and R³ are —OCH₃ and R⁷, R⁸, R⁹ and R¹⁰ are hydrogen, then R⁶ is not—OCH₃, or when L¹ and L² are independently unsubstituted C₁-C₃ alkylene,R² and R³ are —OCH₃, and R⁶, R⁸, R⁹ and R¹⁰ are hydrogen, then R⁷ is not—OCH₃.

Embodiment 8

The pharmaceutical composition of embodiment 7, wherein: L¹ and L² are—CH₂—; R¹, R², R⁴, R⁵, R⁶, R⁷, R⁸, R⁹ and R¹⁰ are independentlyhydrogen, halogen, —OCH₃ or —OCH₂CH₃; and R³ is hydrogen, —OCH₃ or—OCH₂CH₃.

Embodiment 9

The pharmaceutical composition of embodiment 7 or 8, wherein: L¹ and L²are —CH₂—; R², R³, R⁶ and R⁷ are independently hydrogen, halogen, —OCH₃or —OCH₂CH₃; R³ is hydrogen, —OCH₃ or —OCH₂CH₃; and R¹, R⁴, R⁵, R⁸, R⁹and R¹⁰ are hydrogen.

Embodiment 10

The pharmaceutical composition of embodiment 7, 8 or 9, wherein R² andR³ are —OCH₃.

Embodiment 11

The pharmaceutical composition of embodiment 7, 8, 9 or 10, wherein R⁶and R⁷ are independently chlorine or fluorine.

Embodiment 12

The pharmaceutical composition of embodiment 7, 8, 9 or 10, wherein R⁶is —OCH₂CH₃ and R⁷ is hydrogen.

Embodiment 13

The pharmaceutical composition of embodiment 7, 8, 9, 10, 11 or 12,wherein the compound is:

Embodiment 14

A pharmaceutical composition, comprising a pharmaceutically acceptableexcipient and a compound selected from the group consisting of:

Embodiment 15

A method of treating constipation, comprising administering to a subjectin need thereof a therapeutically effective amount a compound ofstructural Formula (I):

or a pharmaceutically acceptable salt thereof, wherein: Ar issubstituted or unsubstituted aryl or substituted or unsubstitutedheteroaryl; L¹ and L² are independently substituted or unsubstitutedC₁-C₃ alkylene; n1, n2, n3, n4 and n5 are independently an integer from0 to 4; m1, m2, m3, m4, m5, v1, v2, v3, v4 and v5 are independently 1 or2; R¹ is hydrogen, halogen, —CX^(1.1) ₃, —CHX^(1.1) ₂, —CH₂X^(1.1), —CN,—SO_(n1)R^(1A), —SO_(v1)NR^(1B)R^(1C), —NHNR^(1B)R^(1C),—ONR^(1B)R^(1C), —NHC(O)NHNR^(1B)R^(1C), —NHC(O)NR^(1B)R^(1C),—N(O)_(m1), —NR^(1B)R^(1C), —C(O)R^(1D), —C(O)OR^(1D),—C(O)NR^(1B)R^(1C), —OR^(1A), —NR^(1B)SO₂R^(1A), —NR^(1B)C(O)R^(1D),—NR^(1B)C(O)OR^(1D), —NR^(1B)OR^(1D), —OCX^(1.1) ₃, —OCHX^(1.1) ₂,substituted or unsubstituted alkyl, substituted or unsubstitutedheteroalkyl, substituted or unsubstituted cycloalkyl, substituted orunsubstituted heterocycloalkyl, substituted or unsubstituted aryl, orsubstituted or unsubstituted heteroaryl; R² is hydrogen, halogen,—CX^(2.1) ₃, —CHX^(2.1) ₂, —CH₂X^(2.1), —CN, —SO_(n2)R^(2A),—SO_(v2)NR^(2B)R^(2C), —NHNR^(2B)R^(2C), ONR^(2B)R^(2C),—NHC(O)NHNR^(2B)R^(2C), —NHC(O)NR^(2B)R^(2C), —N(O)_(m2),—NR^(2B)R^(2C), —C(O)R^(2D), —C(O)OR^(2D), C(O)NR^(2B)R^(2C), —OR^(2A),—NR^(2B)SO₂R^(2A), —NR^(2B)C(O)R^(2D), —NR^(2B)C(O)OR^(2D),—NR^(2B)OR^(2D), —OCX^(2.1) ₃, —OCHX^(2.1) ₂, substituted orunsubstituted alkyl, substituted or unsubstituted heteroalkyl,substituted or unsubstituted cycloalkyl, substituted or unsubstitutedheterocycloalkyl, substituted or unsubstituted aryl, or substituted orunsubstituted heteroaryl; R³ is hydrogen, halogen, —CX^(3.1) ₃,—CHX^(3.1) ₂, —CH₂X^(3.1), —CN, —SO_(n3)R^(3A), —SO_(v3)NR^(3B)R^(3C),—NHNR^(3B)R^(3C), —ONR^(3B)R^(3C), —NHC(O)NHNR^(3B)R^(3C),—NHC(O)NR^(3B)R^(3C), —N(O)_(m3), —NR^(3B)R^(3C), —C(O)R^(3D),—C(O)OR^(3D), —C(O)NR^(3B)R^(3C), —OR^(3A), —NR^(3B)SO₂R^(3A),—NR^(3B)C(O)R^(3D), —NR^(3B)C(O)OR^(3D), —NR^(3B)OR^(3D), —OCX^(3.1) ₃,—OCHX^(3.1) ₂, substituted or unsubstituted alkyl, substituted orunsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl,substituted or unsubstituted heterocycloalkyl, substituted orunsubstituted aryl, or substituted or unsubstituted heteroaryl; R⁴ ishydrogen, halogen, —CX^(4.1) ₃, —CHX^(4.1) ₂, —CH₂X^(4.1), —CN,—SO_(n4)R^(4A), —SO_(v4)NR^(4B)R^(4C), —NHNR^(4B)R^(4C),—ONR^(4B)R^(4C), —NHC(O)NHNR^(4B)R^(4C), —NHC(O)NR^(4B)R^(4C),—N(O)_(m4), —NR^(4B)R^(4C), —C(O)R^(4D), —C(O)OR^(4D),—C(O)NR^(4B)R^(4C), —OR^(4A), —NR^(4B)SO₂R^(4A), —NR^(4B)C(O)R^(4D),—NR^(4B)C(O)OR^(4D), —NR^(4B)OR^(4D), —OCX^(4.1) ₃, —OCHX^(4.1) ₂,substituted or unsubstituted alkyl, substituted or unsubstitutedheteroalkyl, substituted or unsubstituted cycloalkyl, substituted orunsubstituted heterocycloalkyl, substituted or unsubstituted aryl, orsubstituted or unsubstituted heteroaryl; R⁵ is hydrogen, halogen,—CX^(5.1) ₃, —CHX^(5.1) ₂, —CH₂X^(5.1), —CN, —SO_(n5)R^(5A),—SO_(v5)NR^(5B)R^(5C), —NHNR^(5B)R^(5C), —ONR^(5B)R^(5C),—NHC(O)NHNR^(5B)R^(5C), —NHC(O)NR^(5B)R^(5C), —N(O)_(m5),—NR^(5B)R^(5C), —C(O)R^(5D), —C(O)OR^(5D), —C(O)NR^(5B)R^(5C), —OR^(5A),—NR^(5B)SO₂R^(5A), —NR^(5B)C(O)R^(5D), —NR^(5B)C(O)OR^(5D),—NR^(B)OR^(5D), —OCX^(5.1) ₃, —OCHX^(5.1) ₂, substituted orunsubstituted alkyl, substituted or unsubstituted heteroalkyl,substituted or unsubstituted cycloalkyl, substituted or unsubstitutedheterocycloalkyl, substituted or unsubstituted aryl, or substituted orunsubstituted heteroaryl; R^(1A), R^(1B), R^(1C), R^(1D), R^(2A),R^(2B), R^(2C), R^(2D), R^(3A), R^(3B), R^(3C), R^(3D), R^(4A), R^(4B),R^(4C), R^(4D), R^(5A), R^(5B)R^(5C) and R^(5D) are independentlyhydrogen, halogen, —CF₃, —CCl₃, —CBr₃, —CI₃, —OH, —NH₂, —COOH, —CONH₂,—NO₂, —SH, —SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂, —ONH₂, —NHC(O)NHNH₂,—NHC(O)NH₂, —NHSO₂H, —NHC(O)H, —NHC(O)—OH, —NHOH, —OCF₃, —OCCl₃, —OCBr₃,—OCI₃, —OCHF₂, —OCHCl₂, —OCHBr₂, —OCHI₂, substituted or unsubstitutedalkyl, substituted or unsubstituted heteroalkyl, substituted orunsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl,substituted or unsubstituted aryl, or substituted or unsubstitutedheteroaryl; R^(1B), R^(1C), R^(2B), R^(2C), R^(3B), R^(3C), R^(4B),R^(4C), R^(5B) and R^(5C) substituents bonded to the same nitrogen atommay optionally be joined to form a substituted or unsubstitutedheterocycloalkyl or substituted or unsubstituted heteroaryl; andX^(1.1), X^(2.1), X^(3.1), X^(4.1) and X^(5.1) are independently —Cl,—Br, —I or —F.

Embodiment 16

The method of embodiment 15, further comprising administering to thesubject an anti-constipation agent.

Embodiment 17

The method of embodiment 15 or 16, wherein the compound is administeredorally.

Embodiment 18

The method of embodiment 15, 16 or 17, wherein the constipation isopioid-induced constipation, chronic idiopathic constipation orirritable bowel syndrome with constipation predominance.

Embodiment 19

The method of embodiment 15, 16, 17 or 18, wherein the compound isselected from the group consisting of:

Embodiment 20

A method of treating a dry eye disorder, comprising administering to asubject in need thereof a therapeutically effective amount of a compoundof structural Formula (I):

or a pharmaceutically acceptable salt thereof, L¹ and L² areindependently substituted or unsubstituted C₁-C₃ alkylene; n1, n2, n3,n4 and n5 are independently an integer from 0 to 4; m1, m2, m3, m4, m5,v1, v2, v3, v4 and v5 are independently 1 or 2; R¹ is hydrogen, halogen,—CX^(1.1) ₃, —CHX^(1.1) ₂, —CH₂X^(1.1), —CN, —SO_(n)R^(1A),—SO_(v1)NR^(1B)R^(1C), —NHNR^(1B)R^(1C), —ONR^(1B)R^(1C),—NHC(O)NHNR^(1B)R^(1C), —NHC(O)NR^(1B)R^(1C), —N(O)_(m1),—NR^(1B)R^(1C), —C(O)R^(1D), —C(O)OR^(1D), —C(O)NR^(1B)R^(1C), —OR^(1A),—NR^(1B)SO₂R^(1A), —NR^(1B)C(O)R^(1D), —NR^(1B)C(O)OR^(1D),—NR^(1B)OR^(1D), —OCX^(1.1) ₃, —OCHX^(1.1) ₂, substituted orunsubstituted alkyl, substituted or unsubstituted heteroalkyl,substituted or unsubstituted cycloalkyl, substituted or unsubstitutedheterocycloalkyl, substituted or unsubstituted aryl, or substituted orunsubstituted heteroaryl; R² is hydrogen, halogen, —CX^(2.1) ₃,—CHX^(2.1) ₂, —CH₂X^(2.1), —CN, —SO_(n2)R^(2A), —SO_(v2)NR^(2B)R^(2C),—NHNR^(2B)R^(2C), —ONR^(2B)R^(2C), —NHC(O)NHNR^(2B)R^(2C),—NHC(O)NR^(2B)R^(2C), —N(O)_(m2), —NR^(2B)R^(2C), —C(O)R^(2D),—C(O)OR^(2D), —C(O)NR^(2B)R^(2C), —OR^(2A), —NR^(2B)SO₂R^(2A),—NR^(2B)C(O)R^(2D), —NR^(2B)C(O)OR^(2D), —NR^(2B)OR^(2D), —OCX^(2.1) ₃,—OCHX^(2.1) ₂, substituted or unsubstituted alkyl, substituted orunsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl,substituted or unsubstituted heterocycloalkyl, substituted orunsubstituted aryl, or substituted or unsubstituted heteroaryl; R³ ishydrogen, halogen, —CX^(3.1) ₃, —CHX^(3.1) ₂, —CH₂X^(3.1), —CN,—SO_(n3)R^(3A), —SO_(v3)NR^(3B)R^(3C), —NHNR^(3B)R^(3C), ONR^(3B)R^(3C),—NHC(O)NHNR^(3B)R^(3C), —NHC(O)NR^(3B)R^(3C), —N(O)_(m3),—NR^(3B)R^(3C), —C(O)R^(3D), —C(O)OR^(3D), —C(O)NR^(3B)R^(3C), —OR^(3A),—NR^(3B)SO₂R^(3A), —NR^(3B)C(O)R^(3D), —NR^(3B)C(O)OR^(3D),—NR^(3B)OR^(3D), —OCX^(3.1) ₃, —OCHX^(3.1) ₂, substituted orunsubstituted alkyl, substituted or unsubstituted heteroalkyl,substituted or unsubstituted cycloalkyl, substituted or unsubstitutedheterocycloalkyl, substituted or unsubstituted aryl, or substituted orunsubstituted heteroaryl; R⁴ is hydrogen, halogen, —CX^(4.1) ₃,—CHX^(4.1) ₂, —CH₂X^(4.1), —CN, —SO_(n4)R^(4A), —SO_(v4)NR^(4B)R^(4C),—NHNR^(4B)R^(4C), —ONR^(4B)R^(4C), —NHC(O)NHNR^(4B)R^(4C),—NHC(O)NR^(4B)R^(4C), —N(O)_(m4), —NR^(4B)R^(4C), —C(O)R^(4D),—C(O)OR^(4D), —C(O)NR^(4B)R^(4C), —OR^(4A), —NR^(4B)SO₂R^(4A),—NR^(4B)C(O)R^(4D), —NR^(4B)C(O)OR^(4D), —NR^(4B)OR^(4D), —OCX^(4.1) ₃,—OCHX^(4.1) ₂, substituted or unsubstituted alkyl, substituted orunsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl,substituted or unsubstituted heterocycloalkyl, substituted orunsubstituted aryl, or substituted or unsubstituted heteroaryl; R⁵ ishydrogen, halogen, —CX^(5.1) ₃, —CHX^(5.1) ₂, —CH₂X^(5.1), —CN,—SO_(n5)R^(5A), —SO_(v5)NR^(5B)R^(5C), —NHNR^(5B)R^(5C),—ONR^(5B)R^(5C), —NHC(O)NHNR^(5B)R^(5C), —NHC(O)NR^(5B)R^(5C),—N(O)_(m5), —NR^(5B)R^(5C), —C(O)R^(5D), —C(O)OR^(5D),—C(O)NR^(5B)R^(5C), —OR^(5A), —NR^(5B)SO₂R^(5A), —NR^(5B)C(O)R^(5D),—NR^(5B)C(O)OR^(5D), —R^(B)OR^(5D), —OCX^(5.1) ₃, —OCHX^(5.1) ₂,substituted or unsubstituted alkyl, substituted or unsubstitutedheteroalkyl, substituted or unsubstituted cycloalkyl, substituted orunsubstituted heterocycloalkyl, substituted or unsubstituted aryl, orsubstituted or unsubstituted heteroaryl; R^(1A), R^(1B), R^(1C), R^(1D),R^(2A), R^(2B), R^(2C), R^(2D), R^(3A), R^(3B), R^(3C), R^(3D), R^(4A),R^(4B), R^(4C), R^(4D), R^(5A), R^(5B), R^(5C) and R^(5D) areindependently hydrogen, halogen, —CF₃, —CCl₃, —CBr₃, —CI₃, —OH, —NH₂,—COOH, —CONH₂, —NO₂, —SH, —SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂, —ONH₂,—NHC(O)NHNH₂, —NHC(O)NH₂, —NHSO₂H, —NHC(O)H, —NHC(O)—OH, —NHOH, —OCF₃,—OCCl₃, —OCBr₃, —OCI₃, —OCHF₂, —OCHCl₂, —OCHBr₂, —OCHI₂, substituted orunsubstituted alkyl, substituted or unsubstituted heteroalkyl,substituted or unsubstituted cycloalkyl, substituted or unsubstitutedheterocycloalkyl, substituted or unsubstituted aryl, or substituted orunsubstituted heteroaryl; R^(1B), R^(1C), R^(2B), R^(2C), R^(3B),R^(3C), R^(4B), R^(4C), R^(5B) and R^(5C) substituents bonded to thesame nitrogen atom may optionally be joined to form a substituted orunsubstituted heterocycloalkyl or substituted or unsubstitutedheteroaryl; and X^(1.1), X^(2.1), X^(3.1), X^(4.1) and X^(5.1) areindependently —Cl, —Br, —I or —F.

Embodiment 21

The method of embodiment 20, wherein the dry eye disorder is a lacrimalgland disorder.

Embodiment 22

The method of embodiment 20 or 21, further comprising administering tothe subject an anti-dry eye agent.

Embodiment 23

The method of embodiment 20, 21 or 22, wherein the compound is selectedfrom the group consisting of:

Embodiment 24

A method of increasing lacrimation, comprising administering to asubject in need thereof a compound of structural Formula (I):

or a pharmaceutically acceptable salt thereof, wherein: Ar issubstituted or unsubstituted aryl or substituted or unsubstitutedheteroaryl; L¹ and L² are independently substituted or unsubstitutedC₁-C₃ alkylene; n1, n2, n3, n4 and n5 are independently an integer from0 to 4; m1, m2, m3, m4, m5, v1, v2, v3, v4 and v5 are independently 1 or2; R¹ is hydrogen, halogen, —CX^(1.1) ₃, —CHX^(1.1) ₂, —CH₂X^(1.1), —CN,—SO_(n)R^(1A), —SO_(v1)NR^(1B)R^(1C), —NHNR^(1B)R^(1C), —ONR^(1B)R^(1C),—NHC(O)NHNR^(1B)R^(1C), —NHC(O)NR^(1B)R^(1C), —N(O)_(m1),—NR^(1B)R^(1C), —C(O)R^(1D), —C(O)OR^(1D), —C(O)NR^(1B)R^(1C), —OR^(1A),—NR^(1B)SO₂R^(1A), —NR^(1B)C(O)R^(1D), —NR^(1B)C(O)OR^(1D),—NR^(1B)OR^(1D), —OCX^(1.1) ₃, —OCHX^(1.1) ₂, substituted orunsubstituted alkyl, substituted or unsubstituted heteroalkyl,substituted or unsubstituted cycloalkyl, substituted or unsubstitutedheterocycloalkyl, substituted or unsubstituted aryl, or substituted orunsubstituted heteroaryl; R² is hydrogen, halogen, —CX^(2.1) ₃,—CHX^(2.1) ₂, —CH₂X^(2.1), —CN, —SO_(n2)R^(2A), —SO_(v2)NR^(2B)R^(2C),—NHNR^(2B)R^(2C), ONR^(2B)R^(2C), —NHC(O)NHNR^(2B)R^(2C),—NHC(O)NR^(2B)R^(2C), —N(O)_(m2), —NR^(2B)R^(2C), —C(O)R^(2D),—C(O)OR^(2D), C(O)NR^(2B)R^(2C), —OR^(2A), —NR^(2B)SO₂R^(2A),—NR^(2B)C(O)R^(2D), —NR^(2B)C(O)OR^(2D), —NR^(2B)OR^(2D), —OCX^(2.1) ₃,—OCHX^(2.1) ₂, substituted or unsubstituted alkyl, substituted orunsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl,substituted or unsubstituted heterocycloalkyl, substituted orunsubstituted aryl, or substituted or unsubstituted heteroaryl; R³ ishydrogen, halogen, —CX^(3.1) ₃, —CHX^(3.1) ₂, —CH₂X^(3.1), —CN,—SO_(n3)R^(3A), —SO_(v3)NR^(3B)R^(3C), —NHNR^(3B)R^(3C),—ONR^(3B)R^(3C), —NHC(O)NHNR^(3B)R^(3C), —NHC(O)NR^(3B)R^(3C),—N(O)_(m3), —NR^(3B)R^(3C), —C(O)R^(3D), —C(O)OR^(3D),—C(O)NR^(3B)R^(3C), —OR^(3A), —NR^(3B)SO₂R^(3A), —NR^(3B)C(O)R^(3D),—NR^(3B)C(O)OR^(3D), —NR^(3B)OR^(3D), —OCX^(3.1) ₃, —OCHX^(3.1) ₂,substituted or unsubstituted alkyl, substituted or unsubstitutedheteroalkyl, substituted or unsubstituted cycloalkyl, substituted orunsubstituted heterocycloalkyl, substituted or unsubstituted aryl, orsubstituted or unsubstituted heteroaryl; R⁴ is hydrogen, halogen,—CX^(4.1) ₃, —CHX^(4.1) ₂, —CH₂X^(4.1), —CN, —SO_(n4)R^(4A),—SO_(v4)NR^(4B)R^(4C), —NHNR^(4B)R^(4C), —ONR^(4B)R^(4C),—NHC(O)NHNR^(4B)R^(4C), —NHC(O)NR^(4B)R^(4C), —N(O)_(m4),—NR^(4B)R^(4C), —C(O)R^(4D), —C(O)OR^(4D), —C(O)NR^(4B)R^(4C), —OR^(4A),—NR^(4B)SO₂R^(4A), —NR^(4B)C(O)R^(4D), —NR^(4B)C(O)OR^(4D),—NR^(4B)OR^(4D), —OCX^(4.1) ₃, —OCHX^(4.1) ₂, substituted orunsubstituted alkyl, substituted or unsubstituted heteroalkyl,substituted or unsubstituted cycloalkyl, substituted or unsubstitutedheterocycloalkyl, substituted or unsubstituted aryl, or substituted orunsubstituted heteroaryl; R⁵ is hydrogen, halogen, —CX^(5.1) ₃,—CHX^(5.1) ₂, —CH₂X^(5.1), —CN, —SO_(n5)R^(5A), —SO_(v1)NR^(5B)R^(5C),—NHNR^(5B)R^(5C), ONR^(5B)R^(5C), —NHC(O)NHNR^(5B)R^(5C),—NHC(O)NR^(5B)R^(5C), —N(O)_(m5), —NR^(5B)R^(5C), —C(O)R^(5D),—C(O)OR^(5D), —C(O)NR^(5B)R^(5C), —OR^(5A), —NR^(5B)SO₂R^(5A),—NR^(5B)C(O)R^(5D), —NR^(5B)C(O)OR^(5D), —NR^(5B)OR^(5D), —OCX^(5.1) ₃,—OCHX^(5.1) ₂, substituted or unsubstituted alkyl, substituted orunsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl,substituted or unsubstituted heterocycloalkyl, substituted orunsubstituted aryl, or substituted or unsubstituted heteroaryl; R^(1A),R^(1B), R^(1C), R^(1D), R^(2A), R^(2B), R^(2C), R^(2D), R^(3A), R^(3B),R^(3C), R^(3D), R^(4A), R^(4B), R^(4C), R^(4D), R^(5A), R^(5B)R^(5C) andR^(5D) are independently hydrogen, halogen, —CF₃, —CCl₃, —CBr₃, —CI₃,—OH, —NH₂, —COOH, —CONH₂, —NO₂, —SH, —SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂,—ONH₂, —NHC(O)NHNH₂, —NHC(O)NH₂, —NHSO₂H, —NHC(O)H, —NHC(O)—OH, —NHOH,—OCF₃, —OCCl₃, —OCBr₃, —OCI₃, —OCHF₂, —OCHCl₂, —OCHBr₂, —OCHI₂,substituted or unsubstituted alkyl, substituted or unsubstitutedheteroalkyl, substituted or unsubstituted cycloalkyl, substituted orunsubstituted heterocycloalkyl, substituted or unsubstituted aryl, orsubstituted or unsubstituted heteroaryl; R^(1B), R^(1C), R^(2B), R^(2C),R^(3B), R^(3C), R^(4B), R^(4C), R^(5B) and R^(5C) substituents bonded tothe same nitrogen atom may optionally be joined to form a substituted orunsubstituted heterocycloalkyl or substituted or unsubstitutedheteroaryl; and X^(1.1), X^(2.1), X^(3.1), X^(4.1) and X^(5.1) areindependently —Cl, —Br, —I or —F.

Embodiment 25

The method of embodiment 24, wherein the compound is selected from thegroup consisting of:

Embodiment 26

A method of activating Cystic Fibrosis Transmembrane ConductanceRegulator (CFTR), comprising contacting CFTR with a compound ofstructural Formula (I):

or a pharmaceutically acceptable salt thereof, wherein: Ar issubstituted or unsubstituted aryl or substituted or unsubstitutedheteroaryl; L¹ and L² are independently substituted or unsubstitutedC₁-C₃ alkylene; n1, n2, n3, n4 and n5 are independently an integer from0 to 4; m1, m2, m3, m4, m5, v1, v2, v3, v4 and v5 are independently 1 or2; R¹ is hydrogen, halogen, —CX^(1.1) ₃, —CHX^(1.1) ₂, —CH₂X^(1.1), —CN,—SO_(n)R^(1A), —SO_(v1)NR^(1B)R^(1C), —NHNR^(1B)R^(1C), —ONR^(1B)R^(1C),—NHC(O)NHNR^(1B)R^(1C), —NHC(O)NR^(1B)R^(1C), —N(O)_(m1),—NR^(1B)R^(1C), —C(O)R^(1D), —C(O)OR^(1D), —C(O)NR^(1B)R^(1C), —OR^(1A),—NR^(1B)SO₂R^(1A), —NR^(1B)C(O)R^(1D), —NR^(1B)C(O)OR^(1D),—NR^(1B)OR^(1D), —OCX^(1.1) ₃, —OCHX^(1.1) ₂, substituted orunsubstituted alkyl, substituted or unsubstituted heteroalkyl,substituted or unsubstituted cycloalkyl, substituted or unsubstitutedheterocycloalkyl, substituted or unsubstituted aryl, or substituted orunsubstituted heteroaryl; R² is hydrogen, halogen, —CX^(2.1) ₃,—CHX^(2.1) ₂, —CH₂X^(2.1), —CN, —SO_(n2)R^(2A), —SO_(v2)NR^(2B)R^(2C),—NHNR^(2B)R^(2C), ONR^(2B)R^(2C), —NHC(O)NHNR^(2B)R^(2C),—NHC(O)NR^(2B)R^(2C), —N(O)_(m2), —NR^(2B)R^(2C), —C(O)R^(2D),—C(O)OR^(2D), —C(O)NR^(2B)R^(2C), —OR^(2A), —NR^(2B)SO₂R^(2A),—NR^(2B)C(O)R^(2D), —NR^(2B)C(O)OR^(2D), —NR^(2B)OR^(2D), —OCX^(2.1) ₃,—OCHX^(2.1) ₂, substituted or unsubstituted alkyl, substituted orunsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl,substituted or unsubstituted heterocycloalkyl, substituted orunsubstituted aryl, or substituted or unsubstituted heteroaryl; R³ ishydrogen, halogen, —CX^(3.1) ₃, —CHX^(3.1) ₂, —CH₂X^(3.1), —CN,—SO_(n3)R^(3A), —SO_(v3)NR^(3B)R^(3C), —NHNR^(3B)R^(3C), ONR^(3B)R^(3C),—NHC(O)NHNR^(3B)R^(3C), —NHC(O)NR^(3B)R^(3C), —N(O)_(m3),—NR^(3B)R^(3C), —C(O)R^(3D), —C(O)OR^(3D), —C(O)NR^(3B)R^(3C), —OR^(3A),—NR^(3B)SO₂R^(3A), —NR^(3B)C(O)R^(3D), —NR^(3B)C(O)OR^(3D),—NR^(3B)OR^(3D), —OCX^(3.1) ₃, —OCHX^(3.1) ₂, substituted orunsubstituted alkyl, substituted or unsubstituted heteroalkyl,substituted or unsubstituted cycloalkyl, substituted or unsubstitutedheterocycloalkyl, substituted or unsubstituted aryl, or substituted orunsubstituted heteroaryl; R⁴ is hydrogen, halogen, —CX^(4.1) ₃,—CHX^(4.1) ₂, —CH₂X^(4.1), —CN, —SO_(n4)R^(4A), —SO_(v4)NR^(4B)R^(4C),—NHNR^(4B)R^(4C), —ONR^(4B)R^(4C), —NHC(O)NHNR^(4B)R^(4C),—NHC(O)NR^(4B)R^(4C), —N(O)_(m4), —NR^(4B)R^(4C), —C(O)R^(4D),—C(O)OR^(4D), —C(O)NR^(4B)R^(4C), —OR^(4A), —NR^(4B)SO₂R^(4A),—NR^(4B)C(O)R^(4D), —NR^(4B)C(O)OR^(4D), —NR^(4B)OR^(4D), —OCX^(4.1) ₃,—OCHX^(4.1) ₂, substituted or unsubstituted alkyl, substituted orunsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl,substituted or unsubstituted heterocycloalkyl, substituted orunsubstituted aryl, or substituted or unsubstituted heteroaryl; R⁵ ishydrogen, halogen, —CX^(5.1) ₃, —CHX^(5.1) ₂, —CH₂X^(5.1), —CN,—SO_(n5)R^(5A), —SO_(v1)NR^(5B)R^(5C), —NHNR^(5B)R^(5C), ONR^(5B)R^(5C),—NHC(O)NHNR^(5B)R^(5C), —NHC(O)NR^(5B)R^(5C), —N(O)_(m5),—NR^(5B)R^(5C), —C(O)R^(5D), —C(O)OR^(5D), —C(O)NR^(5B)R^(5C), —OR^(5A),—NR^(5B)SO₂R^(5A), —NR^(5B)C(O)R^(5D), —NR^(5B)C(O)OR^(5D),—NR^(5B)OR^(5D), —OCX^(5.1) ₃, —OCHX^(5.1) ₂, substituted orunsubstituted alkyl, substituted or unsubstituted heteroalkyl,substituted or unsubstituted cycloalkyl, substituted or unsubstitutedheterocycloalkyl, substituted or unsubstituted aryl, or substituted orunsubstituted heteroaryl; R^(1A), R^(1B), R^(1C), R^(1D), R^(2A),R^(2B), R^(2C), R^(2D), R^(3A), R^(3B), R^(3C), R^(3D), R^(4A), R^(4B),R^(4C), R^(4D), R^(5A), R^(5B), R^(5C) and R^(5D) are independentlyhydrogen, halogen, —CF₃, —CCl₃, —CBr₃, —CI₃, —OH, —NH₂, —COOH, —CONH₂,—NO₂, —SH, —SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂, —ONH₂, —NHC(O)NHNH₂,—NHC(O)NH₂, —NHSO₂H, —NHC(O)H, —NHC(O)—OH, —NHOH, —OCF₃, —OCCl₃, —OCBr₃,—OCI₃, —OCHF₂, —OCHCl₂, —OCHBr₂, —OCHI₂, substituted or unsubstitutedalkyl, substituted or unsubstituted heteroalkyl, substituted orunsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl,substituted or unsubstituted aryl, or substituted or unsubstitutedheteroaryl; R^(1B), R^(1C), R^(2B), R^(2C), R^(3B), R^(3C), R^(4B),R^(4C), R^(5B) and R^(5C) substituents bonded to the same nitrogen atommay optionally be joined to form a substituted or unsubstitutedheterocycloalkyl or substituted or unsubstituted heteroaryl; andX^(1.1), X^(2.1), X^(3.1), X^(4.1) and X^(5.1) are independently —Cl,—Br, —I or —F.

Embodiment 27

The method of embodiment 26, wherein the compound is selected from thegroup consisting of:

Embodiment 28

A method of treating a cholestatic liver disease in a subject in needthereof, the method comprising administering to the subject an effectiveamount of a compound of Formula (I):

or a pharmaceutically acceptable salt thereof, wherein: Ar issubstituted or unsubstituted aryl or substituted or unsubstitutedheteroaryl; L¹ and L² are independently substituted or unsubstitutedC₁-C₃ alkylene; n1, n2, n3, n4 and n5 are independently an integer from0 to 4; m1, m2, m3, m4, m5, v1, v2, v3, v4 and v5 are independently 1 or2; R¹ is hydrogen, halogen, —CX^(1.1) ₃, —CHX^(1.1) ₂, —CH₂X^(1.1), —CN,—SO_(n1)R^(1A), —SO_(v1)NR^(1B)R^(1C), —NHNR^(1B)R^(1C),—ONR^(1B)R^(1C), —NHC(O)NHNR^(1B)R^(1C), —NHC(O)NR^(1B)R^(1C),—N(O)_(m1), —NR^(1B)R^(1C), —C(O)R^(1D), —C(O)OR^(1D),—C(O)NR^(1B)R^(1C), —OR^(1A), —NR^(1B)SO₂R^(1A), —NR^(1B)C(O)R^(1D),—NR^(1B)C(O)OR^(1D), —NR^(1B)OR^(1D), —OCX^(1.1) ₃, —OCHX^(1.1) ₂,substituted or unsubstituted alkyl, substituted or unsubstitutedheteroalkyl, substituted or unsubstituted cycloalkyl, substituted orunsubstituted heterocycloalkyl, substituted or unsubstituted aryl, orsubstituted or unsubstituted heteroaryl; R² is hydrogen, halogen,—CX^(2.1) ₃, —CHX^(2.1) ₂, —CH₂X^(2.1), —CN, —SO_(n2)R^(2A),—SO₂NR^(2B)R^(2C), —NHNR^(2B)R^(2C), —ONR^(2B)R^(2C),—NHC(O)NHNR^(2B)R^(2C), —NHC(O)NR^(2B)R^(2C), —N(O)_(m2),—NR^(2B)R^(2C), —C(O)R^(2D), —C(O)OR^(2D), —C(O)NR^(2B)R^(2C), —OR^(2A),—NR^(2B)SO₂R^(2A), —NR^(2B)C(O)R^(2D), —NR^(2B)C(O)OR^(2D),—NR^(2B)OR^(2D), —OCX^(2.1) ₃, —OCHX^(2.1) ₂, substituted orunsubstituted alkyl, substituted or unsubstituted heteroalkyl,substituted or unsubstituted cycloalkyl, substituted or unsubstitutedheterocycloalkyl, substituted or unsubstituted aryl, or substituted orunsubstituted heteroaryl; R³ is hydrogen, halogen, —CX^(3.1) ₃,—CHX^(3.1) ₂, —CH₂X^(3.1), —CN, —SO_(n3)R^(3A), —SO_(v3)NR^(3B)R^(3C),—NHNR^(3B)R^(3C), —ONR^(3B)R^(3C), —NHC(O)NHNR^(3B)R^(3C),—NHC(O)NR^(3B)R^(3C), —N(O)_(m3), —NR^(3B)R^(3C), —C(O)R^(3D),—C(O)OR^(3D), —C(O)NR^(3B)R^(3C), —OR^(3A), —NR^(3B)SO₂R^(3A),—NR^(3B)C(O)R^(3D), —NR^(3B)C(O)OR^(3D), —NR^(3B)OR^(3D), —OCX^(3.1) ₃,—OCHX^(3.1) ₂, substituted or unsubstituted alkyl, substituted orunsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl,substituted or unsubstituted heterocycloalkyl, substituted orunsubstituted aryl, or substituted or unsubstituted heteroaryl; R⁴ ishydrogen, halogen, —CX^(4.1) ₃, —CHX^(4.1) ₂, —CH₂X^(4.1), —CN,—SO_(n4)R^(4A), —SO_(v4)NR^(4B)R^(4C), —NHNR^(4B)R^(4C),—ONR^(4B)R^(4C), —NHC(O)NHNR^(4B)R^(4C), —NHC(O)NR^(4B)R^(4C),—N(O)_(m4), —NR^(4B)R^(4C), —C(O)R^(4D), —C(O)OR^(4D),—C(O)NR^(4B)R^(4C), —OR^(4A), —NR^(4B)SO₂R^(4A), —NR^(4B)C(O)R^(4D),—NR^(4B)C(O)OR^(4D), —NR^(4B)OR^(4D), —OCX^(4.1) ₃, —OCHX^(4.1) ₂,substituted or unsubstituted alkyl, substituted or unsubstitutedheteroalkyl, substituted or unsubstituted cycloalkyl, substituted orunsubstituted heterocycloalkyl, substituted or unsubstituted aryl, orsubstituted or unsubstituted heteroaryl; R⁵ is hydrogen, halogen,—CX^(5.1) ₃, —CHX^(5.1) ₂, —CH₂X^(5.1), —CN, —SO_(n5)R^(5A),—SO_(v5)NR^(5B)R^(5C), —NHNR^(5B)R^(5C), —ONR^(5B)R^(5C),—NHC(O)NHNR^(5B)R^(5C), —NHC(O)NR^(5B)R^(5C), —N(O)_(m5),—NR^(5B)R^(5C), —C(O)R^(5D), —C(O)OR^(5D), —C(O)NR^(5B)R^(5C), —OR^(5A),—NR^(5B)SO₂R^(5A), —NR^(5B)C(O)R^(5D), —NR^(5B)C(O)OR^(5D),—NR^(5B)OR^(5D), —OCX^(5.1) ₃, —OCHX^(5.1) ₂, substituted orunsubstituted alkyl, substituted or unsubstituted heteroalkyl,substituted or unsubstituted cycloalkyl, substituted or unsubstitutedheterocycloalkyl, substituted or unsubstituted aryl, or substituted orunsubstituted heteroaryl; R^(1A), R^(1B), R^(1C), R^(1D), R^(2A),R^(2B), R^(2C), R^(2D), R^(3A), R^(3B), R^(3C), R^(3D)R^(4A), R^(4B),R^(4C), R^(4D), R^(5A), R^(5B), R^(5C) and R^(5D) are independentlyhydrogen, halogen, —CF₃, —CCl₃, —CBr₃, —CI₃, —OH, —NH₂, —COOH, —CONH₂,—NO₂, —SH, —SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂, —ONH₂, —NHC(O)NHNH₂,—NHC(O)NH₂, —NHSO₂H, —NHC(O)H, —NHC(O)—OH, —NHOH, —OCF₃, —OCCl₃, —OCBr₃,—OCI₃, —OCHF₂, —OCHCl₂, —OCHBr₂, —OCHI₂, substituted or unsubstitutedalkyl, substituted or unsubstituted heteroalkyl, substituted orunsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl,substituted or unsubstituted aryl, or substituted or unsubstitutedheteroaryl; R^(1B), R^(1C), R^(2B), R^(2C), R^(3B), R^(3C), R^(4B),R^(4C), R^(5B) and R^(5C) substituents bonded to the same nitrogen atommay optionally be joined to form a substituted or unsubstitutedheterocycloalkyl or substituted or unsubstituted heteroaryl; andX^(1.1), X^(2.1), X^(3.1), X^(4.1) and X^(5.1) are independently —Cl,—Br, —I or —F.

Embodiment 29

The method of embodiment 28, wherein the compound is selected from thegroup consisting of:

Embodiment 30

A method of treating a pulmonary disease or disorder in a subject inneed thereof, the method comprising administrating to the subject aneffective amount of a compound of Formula I:

or a pharmaceutically acceptable salt thereof, wherein: Ar issubstituted or unsubstituted aryl or substituted or unsubstitutedheteroaryl; L¹ and L² are independently substituted or unsubstitutedC₁-C₃ alkylene; n1, n2, n3, n4 and n5 are independently an integer from0 to 4; m1, m2, m3, m4, m5, v1, v2, v3, v4 and v5 are independently 1 or2; R¹ is hydrogen, halogen, —CX^(1.1) ₃, —CHX^(1.1) ₂, —CH₂X^(1.1), —CN,—SO_(n1)R^(1A), —SO_(v1)NR^(1B)R^(1C), —NHNR^(1B)R^(1C),—ONR^(1B)R^(1C), —NHC(O)NHNR^(1B)R^(1C), —NHC(O)NR^(1B)R^(1C),—N(O)_(m1), —NR^(1B)R^(1C), —C(O)R^(1D), —C(O)OR^(1D),—C(O)NR^(1B)R^(1C), —OR^(1A), —NR^(1B)SO₂R^(1A), —NR^(1B)C(O)R^(1D),—NR^(1B)C(O)OR^(1D), —NR^(1B)OR^(1D), —OCX^(1.1) ₃, —OCHX^(1.1) ₂,substituted or unsubstituted alkyl, substituted or unsubstitutedheteroalkyl, substituted or unsubstituted cycloalkyl, substituted orunsubstituted heterocycloalkyl, substituted or unsubstituted aryl, orsubstituted or unsubstituted heteroaryl; R² is hydrogen, halogen,—CX^(2.1) ₃, —CHX^(2.1) ₂, —CH₂X^(2.1), —CN, —SO_(n2)R^(2A),—SO₂NR^(2B)R^(2C), —NHNR^(2B)R^(2C), —ONR^(2B)R^(2C),—NHC(O)NHNR^(2B)R^(2C), —NHC(O)NR^(2B)R^(2C), —N(O)_(m2),—NR^(2B)R^(2C), —C(O)R^(2D), —C(O)OR^(2D), —C(O)NR^(2B)R^(2C), —OR^(2A),—NR^(2B)SO₂R^(2A), —NR^(2B)C(O)R^(2D), —NR^(2B)C(O)OR^(2D),—NR^(2B)OR^(2D), —OCX^(2.1) ₃, —OCHX^(2.1) ₂, substituted orunsubstituted alkyl, substituted or unsubstituted heteroalkyl,substituted or unsubstituted cycloalkyl, substituted or unsubstitutedheterocycloalkyl, substituted or unsubstituted aryl, or substituted orunsubstituted heteroaryl; R³ is hydrogen, halogen, —CX^(3.1) ₃,—CHX^(3.1) ₂, —CH₂X^(3.1), —CN, —SO_(n3)R^(3A), —SO_(v3)NR^(3B)R^(3C),—NHNR^(3B)R^(3C), —ONR^(3B)R^(3C), —NHC(O)NHNR^(3B)R^(3C),—NHC(O)NR^(3B)R^(3C), —N(O)_(m3), —NR^(3B)R^(3C), —C(O)R^(3D),—C(O)OR^(3D), —C(O)NR^(3B)R^(3C), —OR^(3A), —NR^(3B)SO₂R^(3A),—NR^(3B)C(O)R^(3D), —NR^(3B)C(O)OR^(3D), —NR^(3B)OR^(3D), —OCX^(3.1) ₃,—OCHX^(3.1) ₂, substituted or unsubstituted alkyl, substituted orunsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl,substituted or unsubstituted heterocycloalkyl, substituted orunsubstituted aryl, or substituted or unsubstituted heteroaryl; R⁴ ishydrogen, halogen, —CX^(4.1) ₃, —CHX^(4.1) ₂, —CH₂X^(4.1), —CN,—SO_(n4)R^(4A), —SO_(v4)NR^(4B)R^(4C), —NHNR^(4B)R^(4C),—ONR^(4B)R^(4C), —NHC(O)NHNR^(4B)R^(4C), —NHC(O)NR^(4B)R^(4C),—N(O)_(m4), —NR^(4B)R^(4C), —C(O)R^(4D), —C(O)OR^(4D),—C(O)NR^(4B)R^(4C), —OR^(4A), —NR^(4B)SO₂R^(4A), —NR^(4B)C(O)R^(4D),—NR^(4B)C(O)OR^(4D), —NR^(4B)OR^(4D), —OCX^(4.1) ₃, —OCHX^(4.1) ₂,substituted or unsubstituted alkyl, substituted or unsubstitutedheteroalkyl, substituted or unsubstituted cycloalkyl, substituted orunsubstituted heterocycloalkyl, substituted or unsubstituted aryl, orsubstituted or unsubstituted heteroaryl; R⁵ is hydrogen, halogen,—CX^(5.1) ₃, —CHX^(5.1) ₂, —CH₂X^(5.1), —CN, —SO_(n5)R^(5A),—SO_(v5)NR^(5B)R^(5C), —NHNR^(5B)R^(5C), —ONR^(5B)R^(5C),—NHC(O)NHNR^(5B)R^(5C), —NHC(O)NR^(5B)R^(5C), —N(O)_(m5),—NR^(5B)R^(5C), —C(O)R^(5D), —C(O)OR^(5D), —C(O)NR^(5B)R^(5C), —OR^(5A),—NR^(5B)SO₂R^(5A), —NR^(5B)C(O)R^(5D), —NR^(5B)C(O)OR^(5D),—NR^(5B)OR^(5D), —OCX^(5.1) ₃, —OCHX^(5.1) ₂, substituted orunsubstituted alkyl, substituted or unsubstituted heteroalkyl,substituted or unsubstituted cycloalkyl, substituted or unsubstitutedheterocycloalkyl, substituted or unsubstituted aryl, or substituted orunsubstituted heteroaryl; R^(1A), R^(1B), R^(1C), R^(1D), R^(2A),R^(2B), R^(2C), R^(2D), R^(3A), R^(3B), R^(3C), R^(3D), R^(4A), R^(4B),R^(4C), R^(4D), R^(5A), R^(5B), R^(5C) and R^(5D) are independentlyhydrogen, halogen, —CF₃, —CCl₃, —CBr₃, —CI₃, —OH, —NH₂, —COOH, —CONH₂,—NO₂, —SH, —SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂, —ONH₂, —NHC(O)NHNH₂,—NHC(O)NH₂, —NHSO₂H, —NHC(O)H, —NHC(O)—OH, —NHOH, —OCF₃, —OCCl₃, —OCBr₃,—OCI₃, —OCHF₂, —OCHCl₂, —OCHBr₂, —OCHI₂, substituted or unsubstitutedalkyl, substituted or unsubstituted heteroalkyl, substituted orunsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl,substituted or unsubstituted aryl, or substituted or unsubstitutedheteroaryl; R^(1B), R^(1C), R^(2B), R^(2C), R^(3B), R^(3C), R^(4B),R^(4C), R^(5B) and R^(5C) substituents bonded to the same nitrogen atommay optionally be joined to form a substituted or unsubstitutedheterocycloalkyl or substituted or unsubstituted heteroaryl; andX^(1.1), X^(2.1), X^(3.1), X^(4.1) and X^(5.1) are independently —Cl,—Br, —I or —F.

Embodiment 31

The method of embodiment 30, wherein the pulmonary disease or disorderis chronic obstructive pulmonary disease, bronchitis, asthma, andcigarette smoke-induced lung dysfunction.

Embodiment 32

The method of embodiment 30 or 31, wherein the compound is selected fromthe group consisting of:

Embodiment 33

A method of treating constipation, comprising administering to a subjectin need thereof a therapeutically effective amount a compound in any ofembodiments 1 to 14.

Embodiment 34

The method of embodiment 33, further comprising administering to thesubject an anti-constipation agent.

Embodiment 35

The method of embodiment 33 or 34, wherein the compound is administeredorally.

Embodiment 36

The method of embodiment 33, 34 or 35, wherein the constipation isopioid-induced constipation, chronic idiopathic constipation orirritable bowel syndrome with constipation predominance.

Embodiment 37

A method of treating a dry eye disorder, comprising administering to asubject in need thereof a therapeutically effective amount of a compoundin any of embodiments 1 to 14.

Embodiment 38

The method of embodiment 37, wherein the dry eye disorder is a lacrimalgland disorder.

Embodiment 39

The method of embodiment 37 or 38, further comprising administering tothe subject an anti-dry eye agent.

Embodiment 40

A method of increasing lacrimation, comprising administering to asubject in need thereof a compound in any of embodiments 1 to 14.

Embodiment 41

A method of activating Cystic Fibrosis Transmembrane ConductanceRegulator (CFTR), comprising contacting CFTR with a compound in any ofembodiments 1 to 14.

Embodiment 42

A method of treating a cholestatic liver disease in a subject in needthereof, the method comprising administering to the subject an effectiveamount of a compound in any of embodiments 1 to 14.

Embodiment 43

A method of treating a pulmonary disease or disorder in a subject inneed thereof, the method comprising administrating to the subject aneffective amount of a compound in any of embodiments 1 to 14.

Embodiment 44

The method of embodiment 43, wherein the pulmonary disease or disorderis chronic obstructive pulmonary disease, bronchitis, asthma, andcigarette smoke-induced lung dysfunction.

Embodiment 45

A compound of Formula I:

(I), or a pharmaceutically acceptable salt thereof, wherein: L¹ and L²are —CH₂—; and R¹, R², R³, R⁴ and R⁵ are independently hydrogen, —OCH₃or —OCH₂CH₃.

Embodiment 46

The compound of embodiment 45, wherein R¹, R⁴ and R⁵ are independentlyhydrogen.

Embodiment 47

The compound of embodiment 45 or 46, wherein R² and R³ are —OCH₃.

Embodiment 48

The compound of embodiment 45, 46 or 47 wherein Ar is unsubstituted2-thienyl.

III. EXAMPLES Example 1—Constipation—I

A cell-based high-throughput screen was done for 120,000 drug-like,synthetic small molecules. Active compounds were characterized formechanism of action and one lead compound was tested in aloperamide-induced constipation model in mice.

Several classes of novel CFTR activators were identified, one of which,the phenylquinoxalinone CFTR_(act)-J027, fully activated CFTR chlorideconductance with EC₅₀˜200 nM, without causing elevation of cytoplasmiccAMP. Orally administered CFTR_(act)-J027 normalized stool output andwater content in a loperamide-induced mouse model of constipation withED₅₀˜0.5 mg/kg; CFTR_(act)-J027 was without effect in cystic fibrosismice lacking functional CFTR. Short-circuit current, fluid secretion andmotility measurements in mouse intestine indicated a pro-secretoryaction of CFTR_(act)-J027 without direct stimulation of intestinalmotility. Oral administration of 10 mg/kg CFTR_(act)-J027 showed minimalbioavailability, rapid hepatic metabolism and blood levels <200 nM, andwithout apparent toxicity after chronic administration.

CFTR_(act)-J027 or alternative small-molecule CFTR-targeted activatorsmay be efficacious for the treatment of constipation.

High-throughput screening was done using a diverse collection of 120,000drug-like synthetic compounds obtained from ChemDiv Inc. (San Diego,Calif., USA) and Asinex (Winston-Salem, N.C., USA). Forstructure-activity analysis, 600 commercially available analogs (ChemDivInc.) of active compounds identified in the primary screen were tested.Other chemicals were purchased from Sigma-Aldrich (St. Louis, Mo., USA)unless indicated otherwise.

CFTR_(act)-J027 synthesis. To a solution of o-phenylenediamine (1 g,9.24 mmol) in DMF (30 mL) was added potassium carbonate (2.5 g, 18.4mmol) and benzyl bromide (0.73 mL, 6.2 mmol) then stirred overnight atambient temperature. The reaction mixture was diluted with CH₂Cl₂,washed with water, dried over MgSO₄ and concentrated under reducedpressure. The residue was purified by flash chromatography to give theintermediate N¹-benzylbenzene-1,2-diamine as a brown liquid. ¹H NMR (300MHz, CDCl₃): δ 7.45-7.31 (m, 5H), 6.86-6.69 (m, 4H), 4.35 (s, 2H), 3.50(br, 3H); MS: m/z 199 (M+H). Then, a solution of the intermediate (400mg, 2 mmol) and 5-nitroisatin (380 mg, 2 mmol) in acetic acid (5 mL) wasrefluxed for 2 h. The reaction mixture was cooled to room temperatureand solvent removed under reduced pressure. The residue was dissolvedwith methanol and acetic acid was added to crystallize3-(2-amino-5-nitrophenyl)-1-benzylquinoxalin-2(1H)-one (CFTR_(act)-J027)as a yellow powder with >99% purity. ¹H NMR (300 MHz, DMSO-d6): δ 9.15(d, 1H, J=2.8 Hz), 8.07 (dd, 1H, J=2.7, 9.2 Hz), 7.97 (dd, 1H, J=1.2,7.9 Hz), 7.82 (brs, 2H), 7.60-7.27 (m, 7H), 6.92 (d, 1H, J=9.2 Hz), 5.59(brs, 2H); ¹³C NMR (75 MHz, DMSO-d6): δ 155.0, 154.6, 153.3, 136.3,135.3, 132.8, 132.2, 131.0, 130.0, 129.5, 129.1, 127.7, 127.3, 126.8,124.1, 116.1, 115.9, 115.4, 45.9; MS: m/z 373 (M+H).

Cell culture. Fischer Rat Thyroid (FRT) cells stably co-expressing humanwild-type CFTR and the halide-sensitive yellow fluorescent protein(YFP)-H148Q were generated as previously described [12]. Cells werecultured on plastic in Coon's-modified Ham's F₁₂ medium supplementedwith 10% fetal bovine serum, 2 mM L-glutamine, 100 units/ml penicillin,and 100 μg/ml streptomycin. For high-throughput screening, cells wereplated in black 96-well microplates (Corning-Costar Corp., Corning, NewYork, USA) at a density of 20,000 cells per well. Screening was done24-48 hours after plating.

High-throughput screening. Screening was carried out using a BeckmanCoulter integrated system equipped with a liquid handling system and twoFLUOstar fluorescence plate readers (BMG Labtechnologies, Durham, N.C.,USA), each equipped with dual syringe pumps and 500±10 nm excitation and535±15 nm emission filters (details in ref 12). CFTR- and YFP-expressingFRT cells were grown at 37° C./5% CO₂ for 24-48 hours after plating. Atthe time of assay, cells were washed three times with phosphate-bufferedsaline (PBS) and then incubated for 10 min with 60 μl of PBS containingtest compounds (at 10 μM) and a low concentration of forskolin (125 nM).Each well was assayed individually for I⁻ influx in a plate reader byrecording fluorescence continuously (200 ms per point) for 2 s(baseline) and then for 12 s after rapid (<1 s) addition of 165 μL ofPBS in which 137 mM Cl⁻ was replaced by I⁻. The initiate rate of I⁻influx was computed by determined using exponential regression. Allcompound plates contained negative controls (DMSO vehicle) and positivecontrols (20 μM forskolin).

Short-circuit current measurement. Short-circuit current was measured inFRT cells stably expressing wild-type human CFTR cultured on porousfilters as described [12]. The basolateral solution contained 130 mMNaCl, 2.7 mM KCl, 1.5 mM KH₂PO₄, 1 mM CaCl₂, 0.5 mM MgCl₂, 10 mMglucose, and 10 mM Na-HEPES (pH 7.3, 37° C.). In the apical solution 65mM NaCl was replaced by Na gluconate, and CaCl₂ was increased to 2 mM,and the basolateral membrane was permeabilized with 250 μg/mlamphotericin B. Short-circuit current was measured in freshly harvestedadult mouse colon at 37° C. using symmetrical Krebs-bicarbonate buffer.

cAMP assay. Intracellular cAMP activity was measured using a GloSensorluminescence assay (Promega Corp., Madison, Wisconson, USA). FRT nullcells were stably transfected with the pGloSensor cAMP plasmid andplated onto white 96-well microplates and grown to confluence. Cellswere washed three times with PBS and incubated with 5 μM CFTR_(act)-J027for 10 min in the absence and presence of 100 nM forskolin. cAMP wasassayed according to the manufacturer's instructions.

Pharmacokinetics. All animal experiments were approved by UCSFInstitutional Animal Care and Use Committee. Female CD1 mice weretreated with 10 mg/kg CFTR_(act)-J027 (saline containing 5% DMSO and 10%Kolliphor HS 15) either intraperitoneally (ip) or orally. Blood wascollected at 15, 30, 60, 150, 240 and 360 min after treatment by orbitalpuncture and centrifuged at 5000 rpm for 15 min to separate plasma.Plasma samples (60 μL) were mixed with 300 μL acetonitrile andcentrifuged at 13000 rpm for 20 min, and 90 μL of the supernatant wasused for LC/MS. The solvent system consisted of a linear gradient from 5to 95% acetonitrile over 16 min (0.2 ml/min flow). Mass spectra wasacquired on a mass spectrometer (Waters 2695 and Micromass ZQ) usingelectrospray (+) ionization, mass ranging from 100 to 1500 Da, conevoltage 40 V. Calibration standards were prepared in plasma fromuntreated mice to which known amounts of CFTR_(act)-J027 were added.

In vitro metabolic stability. CFTR_(act)-J027 (5 μM) was incubated forspecified times at 37° C. with mouse liver microsomes (1 mg protein/ml;Sigma-Aldrich) in potassium phosphate buffer (100 mM) containing 1 mMNADPH, as described [13]. The mixture was then chilled on ice, and 0.5ml of ice-cold ethyl acetate was added. Samples were centrifuged for 15min at 3000 rpm, the supernatant evaporated to dryness, and the residuewas dissolved in 100 μL mobile phase (acetonitrile:water, 3:1) for LC/MSand assayed as described above.

Murine model of constipation. Female CD1 mice (age 8-10 weeks) wereadministered loperamide (0.3 mg/kg, ip, Sigma-Aldrich) to produceconstipation. Various amounts of CFTR_(act)-J027 (0.1, 0.3, 1, 3 and 10mg/kg) were given at the same time (for ip administration) or 1 h before(for oral administration) loperamide. Control mice were treated withvehicle only. Some mice were treated orally with lubiprostone (0.5mg/kg, Sigma-Aldrich) or linaclotide (0.5 mg/kg, Toronto ResearchChemicals Inc., Toronto, Ontario, Canada). After loperamide injection,mice were placed individually in metabolic cages with food and waterprovided ad libitum. Stool samples were collected for 3 h, and totalstool weight and number of fecal pellets were quantified. To measurestool water content stool samples were dried at 80° C. for 24 h andwater content was calculated as [wet weight-dry weight]/wet weight.Similar studies were done in cystic fibrosis (CF) mice (ΔF508homozygous) lacking functional CFTR. Some studies were done using thechemically similar but inactive analog of CFTR_(act)-J027,3-(2-amino-5-nitrophenyl)-1-(methyl)-2(1H)-quinoxalinone.

In vivo intestinal transit and ex vivo intestinal contractility.Whole-gut transit time was determined using an orally administeredmarker (200 μL, 5% Evans Blue, 5% gum Arabic) and measuring the time ofits appearance in stool. Mice were administered loperamide andCFTR_(act)-J027 (10 mg/kg) or vehicle intraperitoneally at zero time.For ex vivo contractility measurements, mice were euthanized by avertinoverdose (200 mg/kg, 2,2,2-tribromethanol, Sigma-Aldrich) and ileum andcolon segments of ˜2 cm length were isolated and washed withKrebs-Henseleit buffer. The ends of the intestinal segments were tied,connected to a force transducer (Biopac Systems, Goleta, Calif., USA)and tissues were transferred to an organ chamber (Biopac Systems)containing Krebs-Henseleit buffer at 37° C. aerated with 95% O₂, 5% CO₂.Ileum and colon were stabilized for 60 min with resting tensions of 0.5and 0.2 g respectively, and solutions were changed every 15 min. Effectsof CFTR_(act)-J027 on baseline and loperamide-suppressed isometricintestinal contractions were recorded.

In vivo intestinal secretion and absorption. Mice (wildtype or CF) weregiven access to 5% dextrose water but not solid food for 24 h beforeexperiments. Mice were anesthetized with isoflurane and body temperaturewas maintained during surgery at 36-38° C. using a heating pad. A smallabdominal incision was made to expose the small intestine, and closedmid-jejunal loops (length 2-3 cm) were isolated by sutures. Loops wereinjected with 100 μL vehicle alone or 100 g CFTR_(act)-J027 in vehicle.The abdominal incision was closed with sutures, and mice were allowed torecover from anesthesia. Intestinal loops were removed at 90 min andloop length and weight were measured to quantify fluid secretion.Intestinal absorption was measured in CF mice (to prevent secretion) asdescribed above, except that the loops were removed at 0 or 30 min.Absorption was calculated as 1-(loop weight at 0 min−loop weight at 30min)/loop weight at 0 min.

Chronic administration and toxicity studies. Mice were administered 10mg/kg CFTR_(act)-J027 or vehicle orally once a day for 7 d. One hourafter the final dose mice were treated with loperamide (0.3 mg/kg, ip)and stool was collected for 3 h. In vivo toxicity was assessed in thesemice by measuring lung wet/dry weight ratio, complete blood count(HEMAVET 950FS, Drew Scientific Inc., Florida, USA) and serum chemistry(Idexx Laboratories Inc., Sacramento, Calif., USA) 4 h after the lastCFTR_(act)-J027 dose. In vitro cytotoxicity was measured in FRT cellsincubated with 25 μM CFTR_(act)-J027 for 8 and 24 h. Cytotoxicity wasmeasured by Alamar Blue assay according to the manufacturer'sinstructions (Invitrogen, Carlsbad, Calif., USA).

Statistical analysis. Experiments with two groups were analyzed withStudent's t-test, when there are 3 groups or more analysis was made withone-way analysis of variance and post-hoc Newman-Keuls multiplecomparisons test. P<0.05 was taken as statistically significant.

Example 2—Identification and In Vitro Characterization of Small-MoleculeCFTR Activators

The goal was to identify a potent, CFTR-targeted activator withpro-secretory activity in intestine in order test its efficacy in amouse model of constipation. FIG. 8A summarizes the project strategy.The compounds evaluated here included small molecules identified inprior CFTR activator/potentiator screens [14] and from a new screen ofsynthetic small molecules not tested previously. The most activecompounds emerging from the screen, along with commercially availablechemical analogs, were prioritized based on an initial mechanism ofaction study (assay of cAMP elevation), in vitro toxicity, pro-secretoryaction in mouse intestine, and efficacy in a mouse model ofconstipation. FIG. 8B shows the cell-based plate reader screening methodin which the initial rate of iodide influx was measured in FRT cellsstably expressing human wildtype CFTR and a YFP fluorescent halidesensor following extracellular iodide addition. A CFTR activatorincreases the initial slope of the fluorescence quenching curve.

FIG. 8C shows chemical structures of six classes of CFTR candidateactivators identified from the screens. Based on the criteria listedabove, we focused further studies on CFTR_(act)-J027, a3-phenyl-quinoxalinone with drug-like properties. CFTR_(act)-J027 wassynthesized in pure crystalline form in two steps (FIG. 8D).

Short-circuit current measurements in CFTR-expressing FRT cells showedthat CFTR_(act)-J027 fully activated CFTR (FIG. 9A), as the cAMP agonistforskolin produced no further increase in current, with an EC₅₀˜200 nM(FIG. 9B). Interestingly, CFTR_(act)-J027 was only a weak potentiator ofΔF508-CFTR, as studied in FRT cells expressing ΔF508-CFTR afterovernight incubation with a corrector (FIG. 9C). Cl⁻ secretion infreshly isolated mouse colon showed a concentration-dependent increasein short-circuit current with EC₅₀˜300 nM (FIG. 9D). The increase incurrent at high CFTR_(act)-J027 was further increased by forskolin,which may be a consequence of activation of a basolateral membranecAMP-sensitive K⁺ channel that increases the driving force for apicalmembrane Cl⁻ secretion. The increase in current was fully inhibited by aCFTR-selective inhibitor. FIG. 9E shows that CFTR_(act)-J027 does notelevate cellular cAMP when added alone, and does not further increasecAMP when added together with forskolin, suggesting that CFTR activationinvolves a direct interaction mechanism rather than indirect actionthrough cAMP elevation.

CFTR_(act)-J027 Normalizes Stool Output in a Mouse Model of Constipation

CFTR_(act)-J027 was studied in the well-established loperamide-inducedmouse model of constipation in which stool weight, pellet number andwater content were measured over 3 h following intraperitonealloperamide administration (FIG. 10A). Intraperitoneal administration ofCFTR_(act)-J027 at 10 mg/kg normalized each of the stool parameters.CFTR_(act)-J027 did not affect stool output or water content in control(non-loperamide-treated) mice. Importantly, CFTR_(act)-J027 was withouteffect in cystic fibrosis mice lacking functional CFTR (FIG. 10B), norwas an inactive chemical analog of CFTR_(act)-J027 effective in wildtypemice (FIG. 10C). These results support a CFTR-selective action ofCFTR_(act)-J027. Dose-response studies in mice showed an ED₅₀ of 2 mg/kgin the loperamide model by ip administration of CFTR_(act)-J027 (FIG.10D).

Oral administration of 10 mg/kg CFTR_(act)-J027 1 h prior to loperamideadministration was also effective in normalizing stool output and watercontent in loperamide-treated mice, with no effect in control mice (FIG.11A). The ED₅₀ for oral administration was 0.5 mg/kg, substantiallylower than that for ip administration (FIG. 11B). In parallel studies,oral administration of the approved drugs lubiprostone or linaclotide at250-500 fold greater mg/kg doses than given to humans for treatment ofconstipation, were less effective in normalizing stool output, producing50% and 35% of the maximal CFTR_(act)-J027 response, respectively (FIG.11C).

CFTR_(act)-J027 Actions on Intestinal Transit, Motility and FluidTransport

CFTR_(act)-J027 action on intestinal transit and motility was measuredin vivo and in isolated intestinal strips, respectively. Whole-guttransit time, as measured by appearance of a marker in the stool afterbolus oral gavage at the time of ip loperamide and CFTR_(act)-J027administration, was normalized by CFTR_(act)-J027 (FIG. 12A, leftpanel). CFTR_(act)-J027 had no effect on whole-gut transit time incystic fibrosis mice (right panel). In vitro measurements of intestinalcontraction showed no effect of CFTR_(act)-J027 added alone or in thepresence of 10 μM loperamide in isolated mouse ileum and colon strips(FIG. 12B). CFTR_(act)-J027 may thus increase intestinal transit in vivoby stimulating motility by secretion-induced stretch of the gut wall,without direct effect on intestinal smooth muscle.

To directly investigate the effects of CFTR_(act)-J027 on intestinalfluid secretion and absorption, an in vivo closed-intestinal loop modelwas used. CFTR_(act)-J027 was injected into closed, mid-jejunal loopsand fluid accumulation was measured at 90 min. CFTR_(act)-J027 produceda 140% increase in loop weight/length ratio, indicating fluid secretioninto the intestinal lumen in wild-type mice (FIG. 12C, upper panel), butwas without effect in cystic fibrosis mice (lower panel), supporting aCFTR-selective mechanism of action. A closed-loop model was also used tostudy CFTR_(act)-J027 action on intestinal fluid absorption. Fluidwithout or with CFTR_(act)-J027 was injected into closed, mid-jejunalloops of cystic fibrosis mice (to avoid confounding fluid secretion) andfluid absorption was measured at 30 min. CFTR_(act)-J027 did not affectintestinal fluid absorption (FIG. 12D).

CFTR_(act)-J027 pharmacology and toxicity in mice. The in vitrometabolic stability of CFTR_(act)-J027 was measured by incubation withmouse liver microsomes in the presence of NADPH. CFTR_(act)-J027 wasrapidly metabolized with ˜21 min elimination half-life, with only 7% ofthe original compound remaining at 60 min (FIG. 13A).

Pharmacokinetics was measured in mice following bolus intraperitoneal ororal administration of 10 mg/kg CFTR_(act)-J027. Following ipadministration serum CFTR_(act)-J027 concentration decreased with anelimination half-life of ˜16 min, and was undetectable at 150 min (FIG.13B). Following oral administration serum CFTR_(act)-J027 concentrationreached 180 nM at 30 min and was undetectable at other time points (FIG.13B).

Preliminary toxicological studies of CFTR_(act)-J027 were done in cellcultures and mice. CFTR_(act)-J027, at a concentration of 20 μM near itssolubility limit, did not show cytotoxicity as measured by the AlamarBlue assay (FIG. 13C). In the 7-day treated mice, CFTR_(act)-J027 didnot affect the major serum chemistry and blood parameters (Table 1), nordid it change body weight or produce airway/lung fluid accumulation(FIG. 13D).

Last, to determine whether chronically administered CFTR_(act)-J027retained efficacy, mice were treated orally for 7 days with 10 mg/kgCFTR_(act)-J027 or vehicle, and loperamide was given 1 h after the finaldose. FIG. 13E shows that chronically administered CFTR_(act)-J027remained effective in normalizing stool output and water contentfollowing loperamide.

TABLE 1 Complete blood count and serum chemistries of mice treated for 7days with 10 mg/kg CFTR_(act)-J027 or vehicle orally once per day (mean± S.E., 5 mice per group). Student's t-test. Vehicle CFTR_(act)-J027 Pvalue Hemoglobin (g/dL) 13.3 ± 0.2  12.8 ± 0.3  >0.05 Leukocytes(10³/μL) 1.9 ± 0.3 1.9 ± 0.5 >0.05 Thrombocytes (10³/μL) 790 ± 109 900 ±48  >0.05 Total protein (g/dL) 4.7 ± 0.2 5.2 ± 0.1 >0.05 Albumin (g/dL)2.6 ± 0.1  2.9 ± 0.03 >0.05 Globulin (g/dL) 2.1 ± 0.1 2.2 ± 0.1 >0.05ALT (U/L) 52 ± 16 44 ± 6  >0.05 AST (U/L) 131 ± 17  105 ± 11  >0.05 ALP(U/L)  47 ± 8.5  53 ± 2.5 >0.05 Total bilirubin (mg/dL) 0.1 ± 0   0.1 ±0   >0.05 Glucose (mg/dL) 156 ± 22  164 ± 6  >0.05 Cholesterol (mg/dL)121 ± 14  121 ± 6  >0.05 CK (U/L) 344 ± 85  312 ± 62  >0.05 Sodium(mmol/L)  149 ± 2.3   151 ± 0.7  >0.05 Potassium (mmol/L) 5.0 ± 0.1 4.4± 0.1 >0.05 Chloride (mmol/L) 113 ± 1  115 ± 1  >0.05 Calcium (mg/dL)8.5 ± 0.2  8.5 ± 0.04 >0.05 Phosphorus (mg/dL) 6.6 ± 0.9 6.8 ± 0.3 >0.05BUN (mg/dL) 15.3 ± 3   18.4 ± 1.2  >0.05 Creatinine (mg/dL) 0.2 ± 0  0.2 ± 0   >0.05 Bicarbonate (mmol/L) 15.3 ± 1.6   16 ± 1.7 >0.05

Example 3—Dry Eye—I

Mice. Wild-type (WT) and CF (homozygous ΔF508-CFTR mutant) mice in a CD1genetic background were bred at the University of California SanFrancisco (UCSF) Animal Facility. Mice aged 8 to 12 weeks (25 to 35 g)were used. Female BALB/c mice (7-8 weeks old) were purchased from theHarlan Laboratory (Livermore, Calif., USA). Animal protocols wereapproved by the UCSF Institutional Animal Care and Use Committee andwere in compliance with the ARVO Statement for the Use of Animals inOphthalmic and Vision Research.

Short-circuit current. Fischer rat thyroid (FRT) cells stably expressingwild-type human CFTR were cultured on Snapwell inserts (Corning Costar,Corning N.Y., USA) for short-circuit current (I_(sc)) measurements.After 6-9 days in culture, when the transepithelial resistance was >1000Ω/cm², the inserts were mounted in an Ussing chamber system (WorldPrecision Instruments, Sarasota, Fla., USA). The basolateral solutioncontained 130 mM NaCl, 2.7 mM KCl, 1.5 mM KH₂PO₄, 1 mM CaCl₂, 0.5 mMMgCl₂, 10 mM glucose, and 10 mM Na-HEPES (pH 7.3). In the apical bathingsolution, 65 mM NaCl was replaced by Na gluconate, and CaCl₂ wasincreased to 2 mM. Both solutions were bubbled with air and maintainedat 37° C. The basolateral membrane was permeabilized with 250 μg/mlamphotericin B (26, 27). Hemichambers were connected to a DVC-1000voltage clamp via Ag/AgCl electrodes and 3 M KCl agar bridges for I_(sc)recording.

cAMP and cytotoxicity assays. Intracellular cAMP activity was measuredusing a GloSensor luminescence assay (Promega Corp., Madison, Wis.,USA). FRT cells stably transfected with the pGloSensor cAMP plasmid(Promega Corp.) were cultured in white 96-well microplates (CorningCostar) overnight. Cells were then washed three times with PBS andincubated with 5 μM test compound for 10 min in the absence and presenceof 100 nM forskolin. To assay cytotoxicity, FRT cells were culturedovernight in black 96-well Costar microplate wells and incubated withtest compounds at up to 100 μM (the maximum solubility in PBS) for 1 or24 h. Cytotoxicity was measured by Alamar Blue assay according to themanufacturer's instructions (Invitrogen, Carlsbad, Calif., USA).

Ocular surface potential difference measurements. Open-circuittransepithelial PD were measured continuously in anesthetized mice inresponse to serial perfusions of different solutions over the ocularsurface, as described (21). Mice were anesthetized with Avertin(2,2,2-tribromoethanol, 125 mg/kg intraperitoneal, Sigma-Aldrich, St.Louis, Mo., USA), and core temperature was maintained at 37° C. using aheating pad. Eyes were oriented with the cornea and conjunctiva facingupward and exposed by retracting the eyelid with cross-action forceps.Solutions were isosmolar (320±10 mOsM; compositions provided in ref. 21)and contained 10μ□ □ indomethacin to prevent CFTR activation byprostaglandins. The ocular surface was perfused at 6 mL/min throughplastic tubing using a multireservoir gravity pinch-valve system (ALAScientific, Westbury, N.Y., USA) and variable-flow peristaltic pump(medium flow model; Fisher Scientific, Fair Lawn, N.J., USA). A probecatheter was fixed 1 mm above the cornea using a micropositioner and asuction cannula was positioned 3 mm from the orbit. The measuringelectrode was in contact to the perfusion catheter and connected to ahigh-impedance voltmeter (IsoMilivolt Meter; WPI). The referenceelectrode was grounded via a winged 21-gauge needle filled withisosmolar saline, and inserted subcutaneously in the abdomen. Measuringand reference electrodes consisted of Ag/AgCl with 3 M KCl agar bridges.

Tear secretion. To measure unstimulated tear production, phenol redthreads (Zone-Quick, Oasis Medical, Glendora, Calif., USA) were placedfor 10 s in the lateral canthi of isofluorane-anesthetized mice usingjewelers' forceps. Tear volume was measured as the length of threadwetting, as visualized under a dissecting microscope. Serialmeasurements were used to evaluate compound pharmacodynamics afterapplication of 2-μL drops of compound formulations (50-100 μM compoundin PBS containing 0.5% polysorbate and 0.5% DMSO) comparing to vehicle.

Lissamine green staining. To assess corneal epithelial disruption, 5 μLof lissamine green (LG) dye (1%) was applied to the ocular surface ofisofluorane-anesthetized mice. Photographs of the eye were taken using aNikon Digital camera adapted to an Olympus Zoom Stereo Microscope(Olympus, Center Valley, Pa., USA). Each corneal quadrant was scored ona 3-point scale by one blinded, trained observer, with the extent ofstaining in each quadrant classified as: 0, no staining; 1, sporadic(involving <25% of the total surface) staining; grade 2, diffusepunctate staining (25-75%); and grade 3, coalesced punctate staining(>75%). The total grade is reported as the sum of scores from all fourquadrants, ranging from 0 to 12.

Pharmacokinetics and tissue distribution. To determine the residencetime of CFTR activators in the pre-ocular mouse tear film, compoundswere recovered for liquid chromatography/mass spectroscopy (LC/MS)following single-dose ophthalmic delivery. Three eye washes (3 μL PBSeach) were recovered from the lateral and medial canthi with 5-μLmicrocapillary tubes (Drummond Scientific Co., Broomhall, Pa., USA)after manual eyelid blinking (9). Pooled washes were diluted withacetonitrile/water (1:1) containing 0.1% formic acid and analyzed byLC/MS using an Xterra MS C18 column (2.1 mm×100 mm, 3.5-μm particlesize) connected to a Waters 2695 HPLC solvent delivery system and aWaters Micromass ZQ mass spectrometer with positive electrosprayionization.

To study compound accumulation in systemic tissues, mouse blood, brain,kidney and liver were analyzed after 14 days of three-times dailytopical dosing (0.1 nmol, 2 μL, 50 μM). Blood samples were collectedfrom the left ventricle into K3 EDTA mini-tubes (Greiner, Kremsmunster,Austria) and centrifuged (28). The supernatant was extracted with anequal volume of ethyl acetate and the extract was dried with an airstream. Organs from treated and control mice were removed followingventricular perfusion with heparinized PBS (10 units/mL), weighed, mixedwith acetic acid and water (100 μL/g tissue), and homogenized (29).Ethyl acetate (10 mL/g tissue) was added, samples were vortexed andcentrifuged (3000 rpm for 15 min), and the ethyl acetate-containingsupernatant was evaporated. Residues obtained from organic extracts ofserum and organ homogenates were then reconstituted and analyzed byLC/MS as described above.

Mouse model of dry eye produced by lacrimal gland excision. A lacrimalgland excision (LGE) model of aqueous-deficient dry eye was adapted froma reported method (30). The extraorbital lacrimal gland was exposed oneach side of wild-type female BALB/c mice (7-8 weeks of age) by 3-mmlinear skin incisions. Lacrimal ducts were cauterized and the entiregland was removed bilaterally, avoiding facial vessels and nerves.Incisions were each closed with a single interrupted 6-0 silk suture.Orbital lacrimal tissue remained functional. Eyes with reduced cornealsensation (<5% of mice studied), as identified from neurotrophic cornealulcers within 1 day of LGE, were excluded. Mice were randomized toreceive either treatment (in both eyes) with CFTR_(act)-K089 (0.1 nmol)or vehicle. Mice were treated three times daily (8 AM, 2 PM and 8 PM)for 2 weeks starting on Day 1 after LGE. Tear secretion and LG stainingwere performed immediately prior to, and one hour after the initial doseon day 4, 10 and 14 after LGE.

Statistics. Data are expressed as the mean±standard error of the mean(SEM). For direct comparisons between two means, the two-sided Students't-test was used. For longitudinal measurements of tear secretion and LGscores in the dry eye prevention study, a linear mixed effectsregression was used, adjusting for non-independence of measurementstaken on the same eye and on both eyes of the same animal. Analysis wasconducted in R v.3.2 for Mac (R Foundation for Statistical Computing,Vienna, Austria), using packages lme4 and robustlmm.

Characterization of small-molecule CFTR activators. A cell-basedfunctional high-throughput screen of 120,000 compounds at 10 μMidentified 20 chemical classes of small-molecule activators of wild-typeCFTR that produced >95% of maximal CFTR activation. The screen was donein FRT epithelial cells co-expressing human wild-type CFTR and acytoplasmic YFP halide sensor in 96-well format (26, 31, 32). Secondaryscreening involved I_(sc) measurement in CFTR-expressing FRT cellspretreated with submaximal forskolin (50 nM). Twenty-one compounds fromeight chemical classes produced large increases in I_(sc) at 1μ□(>75% ofmaximal current produced by 20 μM forskolin). A summary of EC₅₀ andV_(max) values for each compound is provided in FIG. 7.

Structures of activators from the four most active chemical classes areshown in FIG. 2A, along with corresponding concentration-dependence datafrom I_(sc) measurements. Each compound fully activated CFTR, as a highconcentration of forskolin produced little further increase in I_(sc)and the increase in I_(sc) was fully inhibited by a CFTR inhibitor,CFTR_(inh)-172. EC₅₀ values ranged from 20-350 nM (FIG. 2B). VX-770showed relatively weak activity against wild-type CFTR (FIG. 2C).CFTR_(act)-K032 and CFTR_(act)-K089 showed incomplete CFTR activation(˜50% V_(max)).

Compounds that directly target CFTR without causing elevation ofcellular cAMP were sought to minimize potential off-target effects (FIG.2D). Compounds producing elevations in intracellular cAMP (from ClassesO, Q, and R), probably by phosphodiesterase inhibition, were excludedfrom further consideration. Nanomolar-potency compounds from Classes B,J and K, which did not increase cAMP, were selected for furthercharacterization in living mice.

CFTR activators increase ocular surface chloride and fluid secretion invivo. An open-circuit potential difference (PD) method developed in ourlab was used to evaluate compound activity at the ocular surface invivo, as depicted in FIG. 3A (21). Cl⁻ channel function was quantifiedby measuring PD during continuous perfusion of the ocular surface with aseries of solutions that imposed a transepithelial Cl⁻ gradient andcontained various channel agonists and/or inhibitors. The ocular surfacewas first perfused with isosmolar saline to record the baseline PD.Amiloride was then added to the perfusate, followed by exchange to a lowCl⁻ solution in which Cl⁻ with an impermeant anion, gluconate. Thesemaneuvers allow for direct visualization of CFTR activation in responseto addition of candidate CFTR activators.

FIG. 3B shows large hyperpolarizations following exposure toCFTR_(act)-B074, CFTR_(act)-J027 and CFTR_(act)-K089, which wereincreased relatively little by forskolin and were reversed byCFTR_(inh)-172. In comparison, VX-770 produced minimal changes in ocularsurface PD (FIG. 3C). FIG. 3D summarizes PD data for indicatedactivators, with data for additional compounds reported in FIG. 7.Control studies done in CF mice lacking functional CFTR showed nochanges in PD following addition of each of the compounds tested, with arepresentative curve shown for CFTR_(act)-K032 (FIG. 3E).

CFTR activators were next tested for their efficacy in augmenting tearproduction in mice. Preliminary experiments identified a standardophthalmic formulation (0.5% polysorbate) that increased compoundsolubility and duration-of-action. Following a single topical dose, theindirect CFTR activators cholera toxin, forskolin, and3-isobutyl-1-methylxanthine (IBMX) substantially increased basal tearsecretion at 30 min, but these effects were transient and undetectableafter 2 hours (FIG. 4A). However, the direct CFTR activators identifiedhere, CFTR_(act)-B074, CFTR_(act)-J027 and CFTR_(act)-K089, increasedtear fluid secretion by approximately two-fold for at least four hours.VX-770 produced little tear secretion (FIG. 4B). Repeated topicaladministrations (three times daily for up to 2 weeks) produced sustainedtear hypersecretion without tachyphylaxis (FIG. 4C). CFTR activators didnot increase tear fluid secretion in CF mice, demonstrating selectiveCFTR targeting (FIG. 4D).

Toxicity and pharmacokinetics. Tear collection methods were validated bydemonstrating reproducible recovery of tetramethylrhodamine dextran (3kDa) from the ocular surface up to six hours after instillation. Thepharmacokinetics of CFTR_(act)-K089 at the ocular surface was determinedby LC/MS of recovered tear washes. Following instillation of 0.1 nmol ofCFTR_(act)-K089 (2 μL, 50 μM) to the ocular surface, 7.9±2.4 pmol and0.011±0.004 pmol were recovered at five min and six hours, respectively(FIG. 5A). The amount of CFTR_(act)-K089 required for 50% CFTRactivation (EC₅₀˜250 nM) lies between the dashed lines, reflectingconcentrations calculated from the highest and lowest reported normaltear volumes in mice (33, 34). The quantity of CFTR_(act)-K089 recoveredfrom tear fluid predicts therapeutic levels for at least six hours. Tearfluid pharmacokinetics of CFTR_(act)-J027 could not be measured becausethe LC/MS sensitivity was low for this compound.

Following two weeks of three times per day dosing, the amounts ofCFTR_(act)-K089 and CFTR_(act)-J027 were below the limits of detection(˜10 and ˜700 fmol, respectively) in mouse blood, brain, liver andkidney, indicating minimal systemic accumulation. The chronicallytreated mice showed no signs of ocular toxicity, as assessed byslit-lamp evaluation for conjunctival hyperemia, anterior chamberinflammation, and lens clarity. LG staining showed no corneal orconjunctival epithelial disruption (FIG. 5B). The compounds alsoproduced no appreciable in vitro cytotoxicity in cell cultures atconcentrations up to 100 μM (FIG. 5C).

CFTR activator prevents dry eye in a lacrimal gland excision model inmice. On the basis of its favorable tear film pharmacokinetics,CFTR_(act)-K089 was selected for testing in a mouse model ofaqueous-deficient dry eye produced by LGE. Following extraorbital LGE inBALB/c mice, CFTR_(act)-K089-treated mice (0.1 nmol, administered threetimes daily) maintained basal tear volume, whereas tear volume fromvehicle-treated mice was significantly reduced at all subsequenttime-points (FIG. 6A), and for at least 30 days. Similar to what wasreported in C57/b16 mice (30), decreased lacrimation in vehicle-treatedBALB/c mice was associated with progressive epithelial disruption fromDay 0 to Day 14, shown pictorially (FIG. 6B top) and quantitatively(FIG. 6C). CFTR_(act)-K089 not only restored tear secretion in LGE micebut remarkably prevented ocular surface epithelial disruption at alltime points (FIG. 6B). Vehicle-treated eyes developed diffuse,progressive corneal epitheliopathy (LG score increase of 7.3±0.6 by Day14), whereas eyes treated with CFTR_(act)-K089 had minimal LG stainingat all time points (LG score change, −0.6±0.6).

Example 4—Constipation II

Abstract. Background & Aims: Constipation is a common clinical problemthat negatively impacts quality of life and is associated withsignificant health care costs. Activation of the cystic fibrosistransmembrane regulator (CFTR) chloride channel is the primary pathwaythat drives fluid secretion in the intestine, which maintainslubrication of luminal contents. We hypothesized that direct activationof CFTR would cause fluid secretion and reverse the excessivedehydration of stool found in constipation. Methods: A cell-basedhigh-throughput screen was done for 120,000 drug-like, synthetic smallmolecules. Active compounds were characterized for mechanism of actionand one lead compound was tested in a loperamide-induced constipationmodel in mice. Results: Several classes of novel CFTR activators wereidentified, one of which, the phenylquinoxalinone CFTR_(act)-J027, fullyactivated CFTR chloride conductance with EC₅₀˜200 nM, without causingelevation of cytoplasmic cAMP. Orally administered CFTR_(act)-J027normalized stool output and water content in a loperamide-induced mousemodel of constipation with ED₅₀-0.5 mg/kg; CFTR_(act)-J027 was withouteffect in cystic fibrosis mice lacking functional CFTR. Short-circuitcurrent, fluid secretion and motility measurements in mouse intestineindicated a pro-secretory action of CFTR_(act)-J027 without directstimulation of intestinal motility. Oral administration of 10 mg/kgCFTR_(act)-J027 showed minimal bioavailability, rapid hepatic metabolismand blood levels <200 nM, and without apparent toxicity after chronicadministration. Conclusions: CFTR_(act)-J027 or alternativesmall-molecule CFTR-targeted activators may be efficacious for thetreatment of constipation.

INTRODUCTION

Constipation is a common clinical complaint in adults and children thatnegatively impacts quality of life. The prevalence of chronicconstipation has been estimated to be 15% in the US population, withannual health-care costs estimated at ˜7 billion dollars with >800million dollars spent on laxatives [1, 2]. The mainstay of constipationtherapy includes laxatives that increase stool bulk, such as solublefiber; create an osmotic load, such as polyethylene glycol; or stimulateintestinal contraction, such as the diphenylmethanes. There are alsosurface laxatives that soften stool such as docusate sodium andprobiotics such as Lactobacillus paracasei [3]. The FDA-approved druglinaclotide, a peptide agonist of the guanylate cyclase C receptor, actsby inhibiting visceral pain, stimulating intestinal motility, andincreasing intestinal secretion [4, 5]. A second approved drug,lubiprostone, a prostaglandin E analog, is thought to activate aputative enterocyte ClC-2 channel [6], though the mechanistic data areless clear. Despite the wide range of therapeutic options, there is acontinued need for safe and effective drugs to treat constipation.

Intestinal fluid secretion involves active Cl⁻ secretion across theenterocyte epithelium through the basolateral membrane Na⁺/K⁺/2Cl⁻cotransporter (NKCC1) and the luminal membrane cystic fibrosistransmembrane regulator (CFTR) Cl⁻ channel and Ca²⁺-activated Cl⁻channel (CaCC). The electrochemical and osmotic forces created by Cl⁻secretion drive Na⁺ and water secretion [7]. In cholera and Traveler'sdiarrhea CFTR is strongly activated by bacterial enterotoxins throughelevation of intracellular cyclic nucleotides [8, 9]. CFTR is anattractive target to increase intestinal fluid secretion in constipationas it is robustly expressed throughout the intestine and its activationstrongly increases intestinal fluid secretion. An activator targetingCFTR directly is unlikely to produce the massive, uncontrolledintestinal fluid secretion seen in cholera because the enterotoxins incholera act irreversibly to produce sustained elevation of cytoplasmiccAMP, which not only activates CFTR but also basolateral K⁺ channels,which increase the electrochemical driving force for Cl⁻ secretion;cholera enterotoxins also inhibit the luminal NHE3 Na⁺/H⁺ exchangerinvolved in intestinal fluid absorption [10, 11].

Motivated by these considerations and the continuing need for safe andeffective drug therapy of constipation, here we report theidentification and characterization of a nanomolar-potency,CFTR-targeted small-molecule activator, and provide proof of concept forits pro-secretory action in intestine and efficacy in constipation.

Methods.

Materials. High-throughput screening was done using a diverse collectionof 120,000 drug-like synthetic compounds obtained from ChemDiv Inc. (SanDiego, Calif., USA) and Asinex (Winston-Salem, N.C., USA). Forstructure-activity analysis, 600 commercially available analogs (ChemDivInc.) of active compounds identified in the primary screen were tested.Other chemicals were purchased from Sigma-Aldrich (St. Louis, Mo., USA)unless indicated otherwise.

CFTR_(act)-J027 synthesis. To a solution of o-phenylenediamine (1 g,9.24 mmol) in DMF (30 mL) was added potassium carbonate (2.5 g, 18.4mmol) and benzyl bromide (0.73 mL, 6.2 mmol) then stirred overnight atambient temperature. The reaction mixture was diluted with CH₂Cl₂,washed with water, dried over MgSO₄ and concentrated under reducedpressure. The residue was purified by flash chromatography to give theintermediate N¹-benzylbenzene-1,2-diamine as a brown liquid. ¹H NMR (300MHz, CDCl₃): δ 7.45-7.31 (m, 5H), 6.86-6.69 (m, 4H), 4.35 (s, 2H), 3.50(br, 3H); MS: m/z 199 (M+H). Then, a solution of the intermediate (400mg, 2 mmol) and 5-nitroisatin (380 mg, 2 mmol) in acetic acid (5 mL) wasrefluxed for 2 h. The reaction mixture was cooled to room temperatureand solvent removed under reduced pressure. The residue was dissolvedwith methanol and acetic acid was added to crystallize3-(2-amino-5-nitrophenyl)-1-benzylquinoxalin-2(1H)-one (CFTR_(act)-J027)as a yellow powder with >99% purity. ¹H NMR (300 MHz, DMSO-d6): δ 9.15(d, 1H, J=2.8 Hz), 8.07 (dd, 1H, J=2.7, 9.2 Hz), 7.97 (dd, 1H, J=1.2,7.9 Hz), 7.82 (brs, 2H), 7.60-7.27 (m, 7H), 6.92 (d, 1H, J=9.2 Hz), 5.59(brs, 2H); ¹³C NMR (75 MHz, DMSO-d6): δ 155.0, 154.6, 153.3, 136.3,135.3, 132.8, 132.2, 131.0, 130.0, 129.5, 129.1, 127.7, 127.3, 126.8,124.1, 116.1, 115.9, 115.4, 45.9; MS: m/z 373 (M+H).

Cell culture. Fischer Rat Thyroid (FRT) cells stably co-expressing humanwild-type CFTR and the halide-sensitive yellow fluorescent protein(YFP)-H148Q were generated as previously described [12]. Cells werecultured on plastic in Coon's-modified Ham's F₁₂ medium supplementedwith 10% fetal bovine serum, 2 mM L-glutamine, 100 units/ml penicillin,and 100 μg/ml streptomycin. For high-throughput screening, cells wereplated in black 96-well microplates (Corning-Costar Corp., Corning, NewYork, USA) at a density of 20,000 cells per well. Screening was done24-48 hours after plating.

High-throughput screening. Screening was carried out using a BeckmanCoulter integrated system equipped with a liquid handling system and twoFLUOstar fluorescence plate readers (BMG Labtechnologies, Durham, N.C.,USA), each equipped with dual syringe pumps and 500±10 nm excitation and535±15 nm emission filters (details in ref 12). CFTR- and YFP-expressingFRT cells were grown at 37° C./5% CO₂ for 24-48 hours after plating. Atthe time of assay, cells were washed three times with phosphate-bufferedsaline (PBS) and then incubated for 10 min with 60 μl of PBS containingtest compounds (at 10 μM) and a low concentration of forskolin (125 nM).Each well was assayed individually for I⁻ influx in a plate reader byrecording fluorescence continuously (200 ms per point) for 2 s(baseline) and then for 12 s after rapid (<1 s) addition of 165 μL ofPBS in which 137 mM Cl⁻ was replaced by I⁻. The initiate rate of I⁻influx was computed by determined using exponential regression. Allcompound plates contained negative controls (DMSO vehicle) and positivecontrols (20 μM forskolin).

Short-circuit current measurement. Short-circuit current was measured inFRT cells stably expressing wild-type human CFTR cultured on porousfilters as described [12]. The basolateral solution contained 130 mMNaCl, 2.7 mM KCl, 1.5 mM KH₂PO₄, 1 mM CaCl₂, 0.5 mM MgCl₂, 10 mMglucose, and 10 mM Na-HEPES (pH 7.3, 37° C.). In the apical solution 65mM NaCl was replaced by Na gluconate, and CaCl₂ was increased to 2 mM,and the basolateral membrane was permeabilized with 250 μg/mlamphotericin B. Short-circuit current was measured in freshly harvestedadult mouse colon at 37° C. using symmetrical Krebs-bicarbonate buffer.

cAMP assay. Intracellular cAMP activity was measured using a GloSensorluminescence assay (Promega Corp., Madison, Wisconson, USA). FRT nullcells were stably transfected with the pGloSensor cAMP plasmid andplated onto white 96-well microplates and grown to confluence. Cellswere washed three times with PBS and incubated with 5 μM CFTR_(act)-J027for 10 min in the absence and presence of 100 nM forskolin. cAMP wasassayed according to the manufacturer's instructions.

Pharmacokinetics. All animal experiments were approved by UCSFInstitutional Animal Care and Use Committee. Female CD1 mice weretreated with 10 mg/kg CFTR_(act)-J027 (saline containing 5% DMSO and 10%Kolliphor HS 15) either intraperitoneally (ip) or orally. Blood wascollected at 15, 30, 60, 150, 240 and 360 min after treatment by orbitalpuncture and centrifuged at 5000 rpm for 15 min to separate plasma.Plasma samples (60 μL) were mixed with 300 μL acetonitrile andcentrifuged at 13000 rpm for 20 min, and 90 μL of the supernatant wasused for LC/MS. The solvent system consisted of a linear gradient from 5to 95% acetonitrile over 16 min (0.2 ml/min flow). Mass spectra wasacquired on a mass spectrometer (Waters 2695 and Micromass ZQ) usingelectrospray (+) ionization, mass ranging from 100 to 1500 Da, conevoltage 40 V. Calibration standards were prepared in plasma fromuntreated mice to which known amounts of CFTR_(act)-J027 were added.

In vitro metabolic stability. CFTR_(act)-J027 (5 μM) was incubated forspecified times at 37° C. with mouse liver microsomes (1 mg protein/ml;Sigma-Aldrich) in potassium phosphate buffer (100 mM) containing 1 mMNADPH, as described [13]. The mixture was then chilled on ice, and 0.5ml of ice-cold ethyl acetate was added. Samples were centrifuged for 15min at 3000 rpm, the supernatant evaporated to dryness, and the residuewas dissolved in 100 μL mobile phase (acetonitrile:water, 3:1) for LC/MSand assayed as described above.

Murine model of constipation. Female CD1 mice (age 8-10 weeks) wereadministered loperamide (0.3 mg/kg, ip, Sigma-Aldrich) to produceconstipation. Various amounts of CFTR_(act)-J027 (0.1, 0.3, 1, 3 and 10mg/kg) were given at the same time (for ip administration) or 1 h before(for oral administration) loperamide. Control mice were treated withvehicle only. Some mice were treated orally with lubiprostone (0.5mg/kg, Sigma-Aldrich) or linaclotide (0.5 mg/kg, Toronto ResearchChemicals Inc., Toronto, Ontario, Canada). After loperamide injection,mice were placed individually in metabolic cages with food and waterprovided ad libitum. Stool samples were collected for 3 h, and totalstool weight and number of fecal pellets were quantified. To measurestool water content stool samples were dried at 80° C. for 24 h andwater content was calculated as [wet weight-dry weight]/wet weight.Similar studies were done in cystic fibrosis (CF) mice (ΔF508homozygous) lacking functional CFTR. Some studies were done using thechemically similar but inactive analog of CFTR_(act)-J027,3-(2-amino-5-nitrophenyl)-1-(methyl)-2(1H)-quinoxalinone.

In vivo intestinal transit and ex vivo intestinal contractility.Whole-gut transit time was determined using an orally administeredmarker (200 μL, 5% Evans Blue, 5% gum Arabic) and measuring the time ofits appearance in stool. Mice were administered loperamide andCFTR_(act)-J027 (10 mg/kg) or vehicle intraperitoneally at zero time.For ex vivo contractility measurements, mice were euthanized by avertinoverdose (200 mg/kg, 2,2,2-tribromethanol, Sigma-Aldrich) and ileum andcolon segments of ˜2 cm length were isolated and washed withKrebs-Henseleit buffer. The ends of the intestinal segments were tied,connected to a force transducer (Biopac Systems, Goleta, Calif., USA)and tissues were transferred to an organ chamber (Biopac Systems)containing Krebs-Henseleit buffer at 37° C. aerated with 95% O₂, 5% CO₂.Ileum and colon were stabilized for 60 min with resting tensions of 0.5and 0.2 g respectively, and solutions were changed every 15 min. Effectsof CFTR_(act)-J027 on baseline and loperamide-suppressed isometricintestinal contractions were recorded.

In vivo intestinal secretion and absorption. Mice (wildtype or CF) weregiven access to 5% dextrose water but not solid food for 24 h beforeexperiments. Mice were anesthetized with isoflurane and body temperaturewas maintained during surgery at 36-38° C. using a heating pad. A smallabdominal incision was made to expose the small intestine, and closedmid-jejunal loops (length 2-3 cm) were isolated by sutures. Loops wereinjected with 100 μL vehicle alone or 100 μg CFTR_(act)-J027 in vehicle.The abdominal incision was closed with sutures, and mice were allowed torecover from anesthesia. Intestinal loops were removed at 90 min andloop length and weight were measured to quantify fluid secretion.Intestinal absorption was measured in CF mice (to prevent secretion) asdescribed above, except that the loops were removed at 0 or 30 min.Absorption was calculated as 1-(loop weight at 0 min−loop weight at 30min)/loop weight at 0 min.

Chronic administration and toxicity studies. Mice were administered 10mg/kg CFTR_(act)-J027 or vehicle orally once a day for 7 d. One hourafter the final dose mice were treated with loperamide (0.3 mg/kg, ip)and stool was collected for 3 h. In vivo toxicity was assessed in thesemice by measuring lung wet/dry weight ratio, complete blood count(HEMAVET 950FS, Drew Scientific Inc., Florida, USA) and serum chemistry(Idexx Laboratories Inc., Sacramento, Calif., USA) 4 h after the lastCFTR_(act)-J027 dose. In vitro cytotoxicity was measured in FRT cellsincubated with 25 μM CFTR_(act)-J027 for 8 and 24 h. Cytotoxicity wasmeasured by Alamar Blue assay according to the manufacturer'sinstructions (Invitrogen, Carlsbad, Calif., USA).

Statistical analysis. Experiments with two groups were analyzed withStudent's t-test, when there are 3 groups or more analysis was made withone-way analysis of variance and post-hoc Newman-Keuls multiplecomparisons test. P<0.05 was taken as statistically significant.

Results.

Identification and in vitro characterization of small-molecule CFTRactivators. The goal was to identify a potent, CFTR-targeted activatorwith pro-secretory activity in intestine in order test its efficacy in amouse model of constipation. FIG. 8A summarizes the project strategy.The compounds evaluated here included small molecules identified inprior CFTR activator/potentiator screens [14] and from a new screen ofsynthetic small molecules not tested previously. The most activecompounds emerging from the screen, along with commercially availablechemical analogs, were prioritized based on an initial mechanism ofaction study (assay of cAMP elevation), in vitro toxicity, pro-secretoryaction in mouse intestine, and efficacy in a mouse model ofconstipation. FIG. 8B shows the cell-based plate reader screening methodin which the initial rate of iodide influx was measured in FRT cellsstably expressing human wildtype CFTR and a YFP fluorescent halidesensor following extracellular iodide addition. A CFTR activatorincreases the initial slope of the fluorescence quenching curve.

FIG. 8C shows chemical structures of six classes of CFTR candidateactivators identified from the screens. Based on the criteria listedabove, we focused further studies on CFTR_(act)-J027, a3-phenyl-quinoxalinone with drug-like properties. CFTR_(act)-J027 wassynthesized in pure crystalline form in two steps (FIG. 8D).

Short-circuit current measurements in CFTR-expressing FRT cells showedthat CFTR_(act)-J027 fully activated CFTR (FIG. 9A), as the cAMP agonistforskolin produced no further increase in current, with an EC₅₀˜200 nM(FIG. 9B). Interestingly, CFTR_(act)-J027 was only a weak potentiator ofΔF508-CFTR, as studied in FRT cells expressing ΔF508-CFTR afterovernight incubation with a corrector (FIG. 9C). Cl⁻ secretion infreshly isolated mouse colon showed a concentration-dependent increasein short-circuit current with EC₅₀ 300 nM (FIG. 9D). The increase incurrent at high CFTR_(act)-J027 was further increased by forskolin,which may be a consequence of activation of a basolateral membranecAMP-sensitive K⁺ channel that increases the driving force for apicalmembrane Cl⁻ secretion. The increase in current was fully inhibited by aCFTR-selective inhibitor. FIG. 9E shows that CFTR_(act)-J027 does notelevate cellular cAMP when added alone, and does not further increasecAMP when added together with forskolin, suggesting that CFTR activationinvolves a direct interaction mechanism rather than indirect actionthrough cAMP elevation.

CFTR_(act)-J027 normalizes stool output in a mouse model ofconstipation. CFTR_(act)-J027 was studied in the well-establishedloperamide-induced mouse model of constipation in which stool weight,pellet number and water content were measured over 3 h followingintraperitoneal loperamide administration (FIG. 10A). Intraperitonealadministration of CFTR_(act)-J027 at 10 mg/kg normalized each of thestool parameters. CFTR_(act)-J027 did not affect stool output or watercontent in control (non-loperamide-treated) mice. Importantly,CFTR_(act)-J027 was without effect in cystic fibrosis mice lackingfunctional CFTR (FIG. 10B), nor was an inactive chemical analog ofCFTR_(act)-J027 effective in wildtype mice (FIG. 10C). These resultssupport a CFTR-selective action of CFTR_(act)-J027. Dose-responsestudies in mice showed an ED₅₀ of 2 mg/kg in the loperamide model by ipadministration of CFTR_(act)-J027 (FIG. 10D).

Oral administration of 10 mg/kg CFTR_(act)-J027 1 h prior to loperamideadministration was also effective in normalizing stool output and watercontent in loperamide-treated mice, with no effect in control mice (FIG.11A). The ED₅₀ for oral administration was 0.5 mg/kg, substantiallylower than that for ip administration (FIG. 11B). In parallel studies,oral administration of the approved drugs lubiprostone or linaclotide at250-500 fold greater mg/kg doses than given to humans for treatment ofconstipation, were less effective in normalizing stool output, producing50% and 35% of the maximal CFTR_(act)-J027 response, respectively (FIG.11C).

CFTR_(act)-J027 actions on intestinal transit, motility and fluidtransport. CFTR_(act)-J027 action on intestinal transit and motility wasmeasured in vivo and in isolated intestinal strips, respectively.Whole-gut transit time, as measured by appearance of a marker in thestool after bolus oral gavage at the time of ip loperamide andCFTR_(act)-J027 administration, was normalized by CFTR_(act)-J027 (FIG.12A, left panel). CFTR_(act)-J027 had no effect on whole-gut transittime in cystic fibrosis mice (right panel). In vitro measurements ofintestinal contraction showed no effect of CFTR_(act)-J027 added aloneor in the presence of 10 μM loperamide in isolated mouse ileum and colonstrips (FIG. 12B). CFTR_(act)-J027 may thus increase intestinal transitin vivo by stimulating motility by secretion-induced stretch of the gutwall, without direct effect on intestinal smooth muscle.

To directly investigate the effects of CFTR_(act)-J027 on intestinalfluid secretion and absorption, an in vivo closed-intestinal loop modelwas used. CFTR_(act)-J027 was injected into closed, mid-jejunal loopsand fluid accumulation was measured at 90 min. CFTR_(act)-J027 produceda 140% increase in loop weight/length ratio, indicating fluid secretioninto the intestinal lumen in wild-type mice (FIG. 12C, upper panel), butwas without effect in cystic fibrosis mice (lower panel), supporting aCFTR-selective mechanism of action. A closed-loop model was also used tostudy CFTR_(act)-J027 action on intestinal fluid absorption. Fluidwithout or with CFTR_(act)-J027 was injected into closed, mid-jejunalloops of cystic fibrosis mice (to avoid confounding fluid secretion) andfluid absorption was measured at 30 min. CFTR_(act)-J027 did not affectintestinal fluid absorption (FIG. 12D).

CFTR_(act)-J027 pharmacology and toxicity in mice. The in vitrometabolic stability of CFTR_(act)-J027 was measured by incubation withmouse liver microsomes in the presence of NADPH. CFTR_(act)-J027 wasrapidly metabolized with ˜21 min elimination half-life, with only 7% ofthe original compound remaining at 60 min (FIG. 13A).

Pharmacokinetics was measured in mice following bolus intraperitoneal ororal administration of 10 mg/kg CFTR_(act)-J027. Following ipadministration serum CFTR_(act)-J027 concentration decreased with anelimination half-life of ˜16 min, and was undetectable at 150 min (FIG.13B). Following oral administration serum CFTR_(act)-J027 concentrationreached 180 nM at 30 min and was undetectable at other time points (FIG.13B).

Preliminary toxicological studies of CFTR_(act)-J027 were done in cellcultures and mice. CFTR_(act)-J027, at a concentration of 20 μM near itssolubility limit, did not show cytotoxicity as measured by the AlamarBlue assay (FIG. 13C). In the 7-day treated mice, CFTR_(act)-J027 didnot affect the major serum chemistry and blood parameters (Table 1,Example 1), nor did it change body weight or produce airway/lung fluidaccumulation (FIG. 13D).

Last, to determine whether chronically administered CFTR_(act)-J027retained efficacy, mice were treated orally for 7 days with 10 mg/kgCFTR_(act)-J027 or vehicle, and loperamide was given 1 h after the finaldose. FIG. 13E shows that chronically administered CFTR_(act)-J027remained effective in normalizing stool output and water contentfollowing loperamide.

DISCUSSION

We identified by high-throughput screening a nanomolar-affinity,small-molecule CFTR activator, CFTR_(act)-J027, and demonstrated itspro-secretory action in mouse intestine and its efficacy in normalizingstool output in a loperamide-induced mouse model of constipation.Constipation remains a significant clinical problem in outpatient andhospitalized settings. Opioid-induced constipation is a common adverseeffect in patients after surgery, undergoing chemotherapy and withchronic pain.

CFTR-targeted activation adds to the various mechanisms of action ofanti-constipation therapeutics. It is notable that pure CFTR activationis able to produce a robust CI current and fluid secretion response inthe intestine, without causing global elevation of cyclic nucleotideconcentration, direct stimulation of intestinal contractility, oralteration of intestinal fluid absorption. Linaclotide, a peptideagonist of the guanylate cyclase C receptor that increases intestinalcell cGMP concentration. Linaclotide inhibits activation of colonicsensory neurons and activates motor neurons, which reduces pain andincreases intestinal smooth muscle contraction; in addition, elevationin cGMP concentration in enterocytes may activate CFTR and have apro-secretory action [4, 5]. A second approved drug, the prostaglandin Eanalog lubiprostone, is thought to activate a putative enterocyte ClC-2channel [6], though the mechanistic data are less clear. Compared withthese drugs, a pure CFTR activator has a single, well-validatedmechanism of action and does not produce a global cyclic nucleotideresponse in multiple cell types. Of note, linaclotide and lubiprostoneshowed limited efficacy in clinical trials. Linaclotide was effective in˜20% of chronic constipation patients of whom ˜5% also responded toplacebo [15], and lubiprostone was effective in ˜13% of IBS-C patientsof whom ˜7% responded to placebo [16]. Based on our mouse data showingsubstantially greater efficacy of CFTR_(act)-J027 compared tosupramaximal doses of linaclotide or lubiprostone, we speculate thatCFTR activators may have greater efficacy in clinical trials.

CFTR_(act)-J027 is substantially more potent for activation of wildtypeCFTR than VX-770 (ivacaftor), the FDA-approved drug for treatment ofcystic fibrosis (CF) caused by certain CFTR gating mutations. In FRTcells expressing wild-type CFTR, short-circuit current measurementshowed nearly full activation of CFTR by CFTR_(act)-J027 at 3 μM whereasVX-770 maximally activated CFTR by only 15%. However, CFTR_(act)-J027was substantially less potent than ivacaftor as a ‘potentiator’ ofdefective chloride channel gating of the most common CF-causingmutation, ΔF508, which is not unexpected, as potentiator efficacy in CFis mutation-specific. In addition to its potential therapeutic utilityfor constipation, a small-molecule activator of wildtype CFTR may beuseful for treatment of chronic obstructive pulmonary disease andbronchitis, asthma, cigarette smoke-induced lung dysfunction, dry eyeand cholestatic liver disease [17-19].

Substituted quinoxalinones were reported as selective antagonists of themembrane efflux transporter multiple-drug-resistance protein 1 [20].Quinoxalinones have also been reported to show anti-diabetic activity bystimulating insulin secretion in pancreatic INS-1 cells [21], andinhibitory activity against serine proteases for potential therapy ofthrombotic disorders [22]. Recently, quinoxalinones have been reportedto inhibit aldose reductase [23]. These reports suggest that thequinoxalinone scaffold has drug-like properties. Synthetically,quinoxalinone can be prepared in one to four steps from commerciallyavailable starting materials [24], which allows facile synthesis oftargeted analogs.

In addition to compound-specific off-target actions, the potentialside-effects profile of a CFTR activator could include pro-secretoryactivity in the airway/lungs and various glandular and other epithelia.Off-target effects for constipation therapy could be limited by oraladministration of a CFTR activator with limited intestinal absorptionand/or rapid systemic clearance to minimize systemic exposure.CFTR_(act)-J027 when administered orally at a high dose (10 mg/kg)showed very low bioavailability with blood levels well below the EC₅₀for CFTR activation, which may be due to first-pass effect as evidencedits rapid in vitro metabolism in liver microsomes. CFTR_(act)-J027 didnot show significant in vitro cytotoxicity at a concentration of 25μM, >100-fold greater than its EC₅₀ for CFTR activation, or in vivotoxicity in mice in a 7-day study at a maximal efficacious dose thatnormalized stool output in the loperamide model of constipation. Thepotentially most significant off-target action, stimulation oflung/airway fluid secretion, was not seen as evidenced by normal lungwater content in the 7-day treated mice. These limited toxicity studiesoffer proof of concept for application of a CFTR activator inconstipation.

In summary, without wishing to be bound by theory, it is believed thatthe data herein provide evidence for the pro-secretory action of a CFTRactivator in mouse intestine and proof of concept for its use intreatment of various types of constipation, which could includeopioid-induced constipation, chronic idiopathic constipation, andirritable bowel syndrome with constipation predominance.

References (Example 4)

-   [1]. Pinto Sanchez M I, Bercik P. Epidemiology and burden of chronic    constipation. Canadian Journal of Gastroenterology 2011, 25(Suppl    B): 11B-15B; [2]. Mugie S M, Di Lorenzo C, Benninga M A.    Constipation in childhood. Nature Reviews Gastroenterology and    Hepatology 2011, 8(9):502-511; [3]. Menees S, Saad R, Chey W D.    Agents that act luminally to treat diarrhoea and constipation.    Nature Reviews Gastroenterology and Hepatology 2012, 9(11):661-674;    [4]. Castro J, Harrington A M, Hughes P A et al. Linaclotide    inhibits colonic nociceptors and relieves abdominal pain via    guanylate cyclase-C and extracellular cyclic guanosine    3′,5′-monophosphate. Gastroenterology 2013, 145(6):1334-1346; [5].    Busby R W, Bryant A P, Bartolini W P et al. Linaclotide, through    activation of guanylate cyclase C, acts locally in the    gastrointestinal tract to elicit enhanced intestinal secretion and    transit. European Journal of Pharmacology 2010, 649(1-3):328-335;    [6]. Fei G, Raehal K, Liu S et al. Lubiprostone reverses the    inhibitory action of morphine on intestinal secretion in Guinea pig    and mouse. Journal of Pharmacology and Experimental Therapeutics    2010, 334(1):333-340; [7]. Thiagarajah J R, Donowitz M, Verkman A S.    Secretory diarrhoea: mechanisms and emerging therapies. Nature    Reviews Gastroenterology and Hepatology 2015, 12(8):446-457; [8].    Field M, Fromm D, Al-Awqati Q et al. Effect of cholera enterotoxin    on ion transport across isolated ileal mucosa. The Journal of    Clinical Investigation 1972, 51(4):796-804; [9]. Rao M C, Guandalini    S, Smith P L et al. Mode of action of heat-stable Escherichia coli    enterotoxin Tissue and subcellular specificities and role of cyclic    GMP. Biochimica et Biophysica Acta (BBA)-General Subjects 1980,    632(1):35-46; [10]. Subramanya S B, Rajendran V M, Srinivasan P et    al. Differential regulation of cholera toxin-inhibited Na—H exchange    isoforms by butyrate in rat ileum. American Journal of    Physiology-Gastrointestinal and Liver Physiology 2007, 293(4):i    857-G863; [11]. Hecht G, Hodges K, Gill R K et al. Differential    regulation of Na⁺/H⁺ exchange isoform activities by    enteropathogenic E. coli in human intestinal epithelial cells.    American Journal of Physiology-Gastrointestinal and Liver Physiology    2004, 287(2):G370-G378; [12]. Galietta L J V, Springsteel M F, Eda M    et al. Novel CFTR chloride channel activators identified by    screening of combinatorial libraries based on flavone and    benzoquinolizinium lead compounds. Journal of Biological Chemistry    2001, 276(23):19723-19728; [13]. Esteva-Font C, Cil O, Phuan P W et    al. Diuresis and reduced urinary osmolality in rats produced by    small-molecule U T-A-selective urea transport inhibitors. The FASEB    Journal 2014, 28(9):3878-3890; [14]. Ma T, Vetrivel L, Yang H et al.    High-affinity activators of cystic fibrosis transmembrane    conductance regulator (CFTR) chloride conductance identified by    high-throughput screening. Journal of Biological Chemistry 2002,    277(40):37235-37241; [15]. Lembo A J, Schneier H A, Shiff S J et al.    Two randomized trials of linaclotide for chronic constipation. New    England Journal of Medicine 2011, 365(6):527-536; [16]. Website:    www.amitizahcp.com; [17]. Gras D, Chanez P, Vachier I et al.    Bronchial epithelium as a target for innovative treatments in    asthma. Pharmacology & Therapeutics 2013, 140(3):290-305; [18].    Srivastava A. Progressive familial intrahepatic cholestasis. Journal    of Clinical and Experimental Hepatology 2014, 4(1):25-36; [19].    Levin M H, Verkman A S. CFTR-regulated chloride transport at the    ocular surface in living mice measured by potential differences.    Investigative Ophthalmology & Visual Science 2005, 46(4):1428-1434;    [20]. Lawrence D S, Copper J E, Smith C D. Structure-activity    studies of substituted quinoxalinones as multiple-drug-resistance    antagonists. Journal of Medicinal Chemistry 2001, 44(4):594-601;    [21]. Botton G, Valeur E, Kergoat M et al. Preparation of    quinoxalinone derivatives as insulin secretion stimulators useful    for the treatment of diabetes. PCT Int Appl2009, WO 2009109258 A1    20090911 (patent); [22]. Dudley D A, Edmunds J J. Preparation of    quinoxalinones as serine protease inhibitors for treatment of    thrombotic disorders. PCT Int Appl 1999:WO 9950254 A9950251 19991007    (patent); [23]. Qin X, Hao X, Han H et al. Design and Synthesis of    potent and multifunctional aldose reductase inhibitors based on    auinoxalinones. Journal of Medicinal Chemistry 2015,    58(3):1254-1267; [24]. Shaw A D, Denning C R, Hulme C. One-pot    two-step synthesis of quinoxalinones and diazepinones via a tandem    oxidative amidation-deprotection-cyclization sequence. Synthesis    2013, 45(4):459-462.

Example 5—Dry Eye—II

Abbreviations: CFTR, cystic fibrosis transmembrane conductanceregulator; cAMP, cyclic adenosine monophosphate; ENaC, epithelial sodiumchannel; YFP, yellow fluorescent protein; CF, cystic fibrosis; FRTcells, Fischer rat thyroid cells; I_(sc), short-circuit current; PD,potential difference; IBMX, 3-isobutyl-1-methylxanthine; fsk, forskolin;LC/MS, liquid chromatography/mass spectroscopy; LG, lissamine green;LGE, lacrimal gland excision.

Abstract. Dry eye disorders, including Sjögren's syndrome, constitute acommon problem in the aging population with limited effectivetherapeutic options available. The cAMP-activated Cl— channel CFTR(cystic fibrosis transmembrane conductance regulator) is a majorpro-secretory chloride channel at the ocular surface. Here, weinvestigated whether compounds that target CFTR can correct the abnormaltear film in dry eye. Small-molecule activators of human wild-type CFTRidentified by high-throughput screening were evaluated in cell cultureand in vivo assays to select compounds that stimulate Cl—driven fluidsecretion across the ocular surface in mice. Anaminophenyl-1,3,5-triazine, CFTR_(act)-K089, fully activated CFTR incell cultures with EC50 ˜250 nM and produced a ˜8.5 mV hyperpolarizationin ocular surface potential difference. When delivered topically,CFTR_(act)-K089 doubled basal tear secretion for four hours and had noeffect in CF mice. CFTR_(act)-K089 showed sustained tear filmbioavailability without detectable systemic absorption. In a mouse modelof aqueous-deficient dry eye produced by lacrimal gland excision,topical administration of 0.1 nmol CFTR_(act)-K089 three times dailyrestored tear secretion to basal levels and fully prevented the cornealepithelial disruption seen in vehicle-treated controls. Our resultssupport potential utility of CFTR-targeted activators as a novelpro-secretory treatment for dry eye.

INTRODUCTION

Dry eye is a heterogeneous group of disorders with common features ofreduced tear volume and tear fluid hyperosmolarity, which lead toinflammation at the ocular surface. The clinical consequences, whichinclude eye discomfort and visual disturbance, represent a major publichealth concern in an aging population. Dry eye affects up to one-thirdof the global population (1), including five million Americans age 50and over (2, 3). The economic burden of dry eye is substantial, withdirect annual health care costs estimated at $3.84 billion dollars inthe United States (4).

Ninety-four percent of surveyed ophthalmologists believe that additionaltreatments are needed for moderate-to-severe dry eye (7).

The ocular surface is a collection of anatomically continuous epithelialand glandular tissues that are functionally linked to maintain the tearfilm (8). While lacrimation contributes the bulk of reflex tearing, thecornea and conjunctiva regulate basal tear volume and composition. Theprincipal determinants of water movement across the ocular surface intothe tear film include apical chloride (Cl⁻) secretion through cAMP- andcalcium (Ca²⁺)-dependent Cl⁻ transporters, and sodium (Na⁺) absorptionlargely though the epithelial Na⁺ channel (ENaC).

The cystic fibrosis transmembrane conductance regulator (CFTR) is acAMP-activated Cl⁻ channel expressed in some secretory epithelial cells,including those in cornea and conjunctiva (14-16). We found substantialcapacity for active CFTR-facilitated Cl⁻ at the ocular surface in mice(21, 22), as subsequently shown in rat conjunctiva (23), providing arational basis for investigation of CFTR activators as a pro-secretorystrategy for dry eye. The only clinically approved CFTR activator,VX-770 (ivacaftor), is indicated for potentiating the channel gating ofcertain CFTR mutants causing CF, but only weakly activates wild-typeCFTR (24, 25).

Here, we evaluated and prioritized novel small-molecule activators ofwild-type CFTR identified by high-throughput screening as potentialtopical therapy for dry eye, with the research strategy summarized inFIG. 1. The goal was to improve upon our previously identified CFTRactivators (26), which lack suitable potency and chemical properties tobe advanced to clinical development, and to demonstrate efficacy ofnewly identified CFTR activator(s) in a mouse model of dry eye.

Materials and Methods.

Mice. Wild-type (WT) and CF (homozygous ΔF508-CFTR mutant) mice in a CD1genetic background were bred at the University of California SanFrancisco (UCSF) Animal Facility. Mice aged 8 to 12 weeks (25 to 35 g)were used. Female BALB/c mice (7-8 weeks old) were purchased from theHarlan Laboratory (Livermore, Calif., USA). Animal protocols wereapproved by the UCSF Institutional Animal Care and Use Committee andwere in compliance with the ARVO Statement for the Use of Animals inOphthalmic and Vision Research.

Short-circuit current. Fischer rat thyroid (FRT) cells stably expressingwild-type human CFTR were cultured on Snapwell inserts (Corning Costar,Corning N.Y., USA) for short-circuit current (I_(sc)) measurements.After 6-9 days in culture, when the transepithelial resistance was >1000Ω/cm², the inserts were mounted in an Ussing chamber system (WorldPrecision Instruments, Sarasota, Fla., USA). The basolateral solutioncontained 130 mM NaCl, 2.7 mM KCl, 1.5 mM KH₂PO₄, 1 mM CaCl₂, 0.5 mMMgCl₂, 10 mM glucose, and 10 mM Na-HEPES (pH 7.3). In the apical bathingsolution, 65 mM NaCl was replaced by Na gluconate, and CaCl₂ wasincreased to 2 mM. Both solutions were bubbled with air and maintainedat 37° C. The basolateral membrane was permeabilized with 250 μg/mlamphotericin B (26, 27). Hemichambers were connected to a DVC-1000voltage clamp via Ag/AgCl electrodes and 3 M KCl agar bridges for I_(sc)recording.

cAMP and cytotoxicity assays. Intracellular cAMP activity was measuredusing a GloSensor luminescence assay (Promega Corp., Madison, Wis.,USA). FRT cells stably transfected with the pGloSensor cAMP plasmid(Promega Corp.) were cultured in white 96-well microplates (CorningCostar) overnight. Cells were then washed three times with PBS andincubated with 5 μM test compound for 10 min in the absence and presenceof 100 nM forskolin. To assay cytotoxicity, FRT cells were culturedovernight in black 96-well Costar microplate wells and incubated withtest compounds at up to 100 μM (the maximum solubility in PBS) for 1 or24 h. Cytotoxicity was measured by Alamar Blue assay according to themanufacturer's instructions (Invitrogen, Carlsbad, Calif., USA).

Ocular surface potential difference measurements. Open-circuittransepithelial PD were measured continuously in anesthetized mice inresponse to serial perfusions of different solutions over the ocularsurface, as described (21). Mice were anesthetized with Avertin(2,2,2-tribromoethanol, 125 mg/kg intraperitoneal, Sigma-Aldrich, St.Louis, Mo., USA), and core temperature was maintained at 37° C. using aheating pad. Eyes were oriented with the cornea and conjunctiva facingupward and exposed by retracting the eyelid with cross-action forceps.Solutions were isosmolar (320±10 mOsM; compositions provided in ref 21)and contained 10 μM indomethacin to prevent CFTR activation byprostaglandins. The ocular surface was perfused at 6 mL/min throughplastic tubing using a multireservoir gravity pinch-valve system (ALAScientific, Westbury, N.Y., USA) and variable-flow peristaltic pump(medium flow model; Fisher Scientific, Fair Lawn, N.J., USA). A probecatheter was fixed 1 mm above the cornea using a micropositioner and asuction cannula was positioned 3 mm from the orbit. The measuringelectrode was in contact to the perfusion catheter and connected to ahigh-impedance voltmeter (IsoMilivolt Meter; WPI). The referenceelectrode was grounded via a winged 21-gauge needle filled withisosmolar saline, and inserted subcutaneously in the abdomen. Measuringand reference electrodes consisted of Ag/AgCl with 3 M KCl agar bridges.

Tear secretion. To measure unstimulated tear production, phenol redthreads (Zone-Quick, Oasis Medical, Glendora, Calif., USA) were placedfor 10 s in the lateral canthi of isofluorane-anesthetized mice usingjewelers' forceps. Tear volume was measured as the length of threadwetting, as visualized under a dissecting microscope. Serialmeasurements were used to evaluate compound pharmacodynamics afterapplication of 2-μL drops of compound formulations (50-100 μM compoundin PBS containing 0.5% polysorbate and 0.5% DMSO) comparing to vehicle.

Lissamine green staining. To assess corneal epithelial disruption, 5 μLof lissamine green (LG) dye (1%) was applied to the ocular surface ofisofluorane-anesthetized mice. Photographs of the eye were taken using aNikon Digital camera adapted to an Olympus Zoom Stereo Microscope(Olympus, Center Valley, Pa., USA). Each corneal quadrant was scored ona 3-point scale by one blinded, trained observer, with the extent ofstaining in each quadrant classified as: 0, no staining; 1, sporadic(involving <25% of the total surface) staining; grade 2, diffusepunctate staining (25-75%); and grade 3, coalesced punctate staining(>75%). The total grade is reported as the sum of scores from all fourquadrants, ranging from 0 to 12.

Pharmacokinetics and tissue distribution. To determine the residencetime of CFTR activators in the pre-ocular mouse tear film, compoundswere recovered for liquid chromatography/mass spectroscopy (LC/MS)following single-dose ophthalmic delivery. Three eye washes (3 μL PBSeach) were recovered from the lateral and medial canthi with 5-μLmicrocapillary tubes (Drummond Scientific Co., Broomhall, Pa., USA)after manual eyelid blinking (9). Pooled washes were diluted withacetonitrile/water (1:1) containing 0.1% formic acid and analyzed byLC/MS using an Xterra MS C18 column (2.1 mm×100 mm, 3.5-μm particlesize) connected to a Waters 2695 HPLC solvent delivery system and aWaters Micromass ZQ mass spectrometer with positive electrosprayionization.

To study compound accumulation in systemic tissues, mouse blood, brain,kidney and liver were analyzed after 14 days of three-times dailytopical dosing (0.1 nmol, 2 μL, 50 μM). Blood samples were collectedfrom the left ventricle into K3 EDTA mini-tubes (Greiner, Kremsmunster,Austria) and centrifuged (28). The supernatant was extracted with anequal volume of ethyl acetate and the extract was dried with an airstream. Organs from treated and control mice were removed followingventricular perfusion with heparinized PBS (10 units/mL), weighed, mixedwith acetic acid and water (100 μL/g tissue), and homogenized (29).Ethyl acetate (10 mL/g tissue) was added, samples were vortexed andcentrifuged (3000 rpm for 15 min), and the ethyl acetate-containingsupernatant was evaporated. Residues obtained from organic extracts ofserum and organ homogenates were then reconstituted and analyzed byLC/MS as described above.

Mouse model of dry eye produced by lacrimal gland excision. A lacrimalgland excision (LGE) model of aqueous-deficient dry eye was adapted froma reported method (30). The extraorbital lacrimal gland was exposed oneach side of wild-type female BALB/c mice (7-8 weeks of age) by 3-mmlinear skin incisions. Lacrimal ducts were cauterized and the entiregland was removed bilaterally, avoiding facial vessels and nerves.Incisions were each closed with a single interrupted 6-0 silk suture.Orbital lacrimal tissue remained functional. Eyes with reduced cornealsensation (<5% of mice studied), as identified from neurotrophic cornealulcers within 1 day of LGE, were excluded. Mice were randomized toreceive either treatment (in both eyes) with CFTR_(act)-K089 (0.1 nmol)or vehicle. Mice were treated three times daily (8 AM, 2 PM and 8 PM)for 2 weeks starting on Day 1 after LGE. Tear secretion and LG stainingwere performed immediately prior to, and one hour after the initial doseon day 4, 10 and 14 after LGE.

Statistics. Data are expressed as the mean±standard error of the mean(SEM). For direct comparisons between two means, the two-sided Students't-test was used. For longitudinal measurements of tear secretion and LGscores in the dry eye prevention study, a linear mixed effectsregression was used, adjusting for non-independence of measurementstaken on the same eye and on both eyes of the same animal. Analysis wasconducted in R v.3.2 for Mac (R Foundation for Statistical Computing,Vienna, Austria), using packages lme4 and robustlmm.

Results.

Characterization of small-molecule CFTR activators. A cell-basedfunctional high-throughput screen of 120,000 compounds at 10 μMidentified 20 chemical classes of small-molecule activators of wild-typeCFTR that produced >95% of maximal CFTR activation. The screen was donein FRT epithelial cells co-expressing human wild-type CFTR and acytoplasmic YFP halide sensor in 96-well format (26, 31, 32). Secondaryscreening involved I_(sc) measurement in CFTR-expressing FRT cellspretreated with submaximal forskolin (50 nM). Twenty-one compounds fromeight chemical classes produced large increases in I_(sc) at 1μ□ (>75%of maximal current produced by 20 μM forskolin). A summary of EC₅₀ andV_(max) values for each compound is provided in FIG. 7.

Structures of activators from the four most active chemical classes areshown in FIG. 2A, along with corresponding concentration-dependence datafrom I_(sc) measurements. Each compound fully activated CFTR, as a highconcentration of forskolin produced little further increase in I_(sc)and the increase in I_(sc) was fully inhibited by a CFTR inhibitor,CFTR_(inh)-172. EC₅₀ values ranged from 20-350 nM (FIG. 2B). VX-770showed relatively weak activity against wild-type CFTR (FIG. 2C).CFTR_(act)-K032 and CFTR_(act)-K089 had lower potency and showed lessCFTR activation (˜50% V_(max)).

Compounds that directly target CFTR without causing elevation ofcellular cAMP were sought to minimize potential off-target effects (FIG.2D). Compounds producing elevations in intracellular cAMP (from ClassesO, Q, and R), probably by phosphodiesterase inhibition, were excludedfrom further consideration. Nanomolar-potency compounds from Classes B,J and K, which did not increase cAMP, were selected for furthercharacterization in living mice.

CFTR activators increase ocular surface chloride and fluid secretion invivo. An open-circuit potential difference (PD) method developed in ourlab was used to evaluate compound activity at the ocular surface invivo, as depicted in FIG. 3A (21). Cl⁻ channel function was quantifiedby measuring PD during continuous perfusion of the ocular surface with aseries of solutions that imposed a transepithelial Cl⁻ gradient andcontained various channel agonists and/or inhibitors. The ocular surfacewas first perfused with isosmolar saline to record the baseline PD.Amiloride was then added to the perfusate, followed by exchange to a lowCl⁻ solution in which Cl⁻ with an impermeant anion, gluconate. Thesemaneuvers allow for direct visualization of CFTR activation in responseto addition of candidate CFTR activators.

FIG. 3B shows large hyperpolarizations following exposure toCFTR_(act)-B074, CFTR_(act)-J027 and CFTR_(act)-K089, which wereincreased relatively little by forskolin and were reversed byCFTR_(inh)-172. In comparison, VX-770 produced minimal changes in ocularsurface PD (FIG. 3C). FIG. 3D summarizes PD data for indicatedactivators, with data for additional compounds reported in FIG. 7.Control studies done in CF mice lacking functional CFTR showed nochanges in PD following addition of each of the compounds tested, with arepresentative curve shown for CFTR_(act)-K032 (FIG. 3E).

CFTR activators were next tested for their efficacy in augmenting tearproduction in mice. Preliminary experiments identified a standardophthalmic formulation (0.5% polysorbate) that increased compoundsolubility and duration-of-action. Following a single topical dose, theindirect CFTR activators cholera toxin, forskolin, and3-isobutyl-1-methylxanthine (IBMX) substantially increased basal tearsecretion at 30 min, but these effects were transient and undetectableafter 2 hours (FIG. 4A). However, the direct CFTR activators identifiedhere, CFTR_(act)-B074, CFTR_(act)-J027 and CFTR_(act)-K089, increasedtear fluid secretion by approximately two-fold for at least four hours.VX-770 produced little tear secretion (FIG. 4B). Repeated topicaladministrations (three times daily for up to 2 weeks) produced sustainedtear hypersecretion without tachyphylaxis (FIG. 4C). CFTR activators didnot increase tear fluid secretion in CF mice, demonstrating selectiveCFTR targeting (FIG. 4D).

Toxicity and pharmacokinetics. Tear collection methods were validated bydemonstrating reproducible recovery of tetramethylrhodamine dextran (3kDa) from the ocular surface up to six hours after instillation. Thepharmacokinetics of CFTR_(act)-K089 at the ocular surface was determinedby LC/MS of recovered tear washes. Following instillation of 0.1 nmol ofCFTR_(act)-K089 (2 μL, 50 μM) to the ocular surface, 7.9±2.4 pmol and0.011±0.004 pmol were recovered at five min and six hours, respectively(FIG. 5A). The amount of CFTR_(act)-K089 required for 50% CFTRactivation (EC₅₀˜250 nM) lies between the dashed lines, reflectingconcentrations calculated from the highest and lowest reported normaltear volumes in mice (33, 34). The quantity of CFTR_(act)-K089 recoveredfrom tear fluid predicts therapeutic levels for at least six hours. Tearfluid pharmacokinetics of CFTR_(act)-J027 could not be measured becausethe LC/MS sensitivity was low for this compound.

Following two weeks of three times per day dosing, the amounts ofCFTR_(act)-K089 and CFTR_(act)-J027 were below the limits of detection(˜10 and ˜700 fmol, respectively) in mouse blood, brain, liver andkidney, indicating minimal systemic accumulation. The chronicallytreated mice showed no signs of ocular toxicity, as assessed byslit-lamp evaluation for conjunctival hyperemia, anterior chamberinflammation, and lens clarity. LG staining showed no corneal orconjunctival epithelial disruption (FIG. 5B). The compounds alsoproduced no appreciable in vitro cytotoxicity in cell cultures atconcentrations up to 100 μM (FIG. 5C).

CFTR activator prevents dry eye in a lacrimal gland excision model inmice. On the basis of its favorable tear film pharmacokinetics,CFTR_(act)-K089 was selected for testing in a mouse model ofaqueous-deficient dry eye produced by LGE. Following extraorbital LGE inBALB/c mice, CFTR_(act)-K089-treated mice (0.1 nmol, administered threetimes daily) maintained basal tear volume, whereas tear volume fromvehicle-treated mice was significantly reduced at all subsequenttime-points (FIG. 6A), and for at least 30 days. Similar to what wasreported in C57/b16 mice (30), decreased lacrimation in vehicle-treatedBALB/c mice was associated with progressive epithelial disruption fromDay 0 to Day 14, shown pictorially (FIG. 6B top) and quantitatively(FIG. 6C). CFTR_(act)-K089 not only restored tear secretion in LGE micebut remarkably prevented ocular surface epithelial disruption at alltime points (FIG. 6B). Vehicle-treated eyes developed diffuse,progressive corneal epitheliopathy (LG score increase of 7.3±0.6 by Day14), whereas eyes treated with CFTR_(act)-K089 had minimal LG stainingat all time points (LG score change, −0.6±0.6).

DISCUSSION

A goal of this study was to investigate the potential utility ofsmall-molecule activators of CFTR for dry eye therapy. After severalprior development failures, dry eye remains an unmet need in oculardisease. In dry eye disorders, tear film hyperosmolarity stimulatespro-inflammatory signaling, secretion of cytokines andmetalloproteinases, and disruption of corneal epithelial cell integrity(35-38). By minimizing tear film hyperosmolarity, CFTR activation ispredicted to prevent these downstream ocular surface changes.

We identified small-molecule CFTR activators by high-throughputscreening that produced sustained Cl⁻-driven aqueous fluid secretionacross the ocular surface by a mechanism involving direct CFTRactivation rather than upstream cAMP signaling. The rationale to choosecompounds that activate CFTR directly was to minimize potentialoff-target effects of generalized cAMP stimulation and to reduce thelikelihood of tachyphylaxis for compounds targeting signaling receptors.These compounds had low-nanomolar EC₅₀ for activation of human CFTR invitro and produced full activation at higher concentrations. LargeCFTR-dependent PD hyperpolarizations and tear hypersecretion weredemonstrated in mice. Substantial compound activities in mice and humanswill facilitate translation of data here to humans.

We found that CFTR_(act)-K089 restored tear secretion and preventedepithelial disruption in an experimental mouse model of lacrimalinsufficiency. CFTR activators may be particularly suited for disordersof the lacrimal gland, such as primary Sjögren's syndrome, bystimulating fluid transport across the intact corneal and conjunctivalepithelia. CFTR activators probably exert their major pro-secretoryeffect at the ocular surface, although there is indirect for CFTRexpression and function in lacrimal gland (39-42). Direct stimulation oflacrimal secretion is unlikely in the studies here because of minimalcompound penetration to lacrimal tissues following topical delivery, andthe demonstrated compound efficacy in a model of lacrimal insufficiency.At the ocular surface, the conjunctiva probably contributes the bulk offluid secretion given its much larger surface area compared to cornea(43).

Alternative pro-secretory therapies targeting different ocular surfaceion channels have been considered. The only FDA-approved CFTR activator,VX-770, was developed as a “potentiator” to treat CF by correcting thechannel gating of certain CFTR mutations (44). However, VX-770 showedrelatively little activity against wild-type CFTR in cell cultures andin mice in vivo. Chronic application of VX-770 may also diminish CFTRfunctional expression (24) and cause cataracts (seen in juvenile rats;ref. 42), which is likely an off-target effect because CFTR is notexpressed in lens.

CFTR_(act)-K089 and CFTR_(act)-J027 showed favorable pharmacodynamicsand could be conveniently administered topically several times daily ina standard ophthalmic formulation.

In conclusion, without wishing to be bound by theory, it is believedthat the efficacy of CFTR_(act)-K089 in a clinically relevant mousemodel of aqueous-deficient dry eye disease provides proof-of-principlefor topical, pro-secretory CFTR activator therapy to restore basal tearsecretion and prevent ocular surface pathology. Compared withimmunosuppressive approaches, CFTR activation has the advantage ofaddressing an early event in dry eye pathogenesis. Our data thus supportthe development potential of CFTR activators as first-in-class dry eyetherapy.

References (Example 5)

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It is understood that the examples and embodiments described herein arefor illustrative purposes only and that various modifications or changesin light thereof will be suggested to persons skilled in the art and areto be included within the spirit and purview of this application andscope of the appended claims. All publications, patents, and patentapplications cited herein are hereby incorporated by reference in theirentirety for all purposes.

1. A method of treating an individual with a disease or conditionselected from the group consisting of (a) constipation, (b) dry eyedisorder, (c) cholestatic liver disease, or (d) a pulmonary disease ordisorder, the method comprising: administering to said individual anamount of the compound of Formula I:

or a pharmaceutically acceptable salt thereof, effective to treat saiddisease or condition, wherein: Ar is substituted or unsubstituted arylor substituted or unsubstituted heteroaryl; L¹ and L² are independentlysubstituted or unsubstituted C₁-C₃ alkylene; n1, n2, n3, n4 and n5 areindependently an integer from 0 to 4; m1, m2, m3, m4, m5, v1, v2, v3, v4and v5 are independently 1 or 2; R¹ is hydrogen, halogen, —CX^(1.1) ₃,—CHX^(1.1) ₂, —CH₂X^(1.1), —CN, —SO_(n1)R^(1A), —SO_(v1)NR^(1B)R^(1C),—NHNR^(1B)R^(1C), —ONR^(1B)R^(1C), —NHC(O)NHNR^(1B)R^(1C),—NHC(O)NR^(1B)R^(1C), —N(O)_(m1), —NR^(1B)R^(1C), —C(O)R^(1D),—C(O)OR^(1D), —C(O)NR^(1B)R^(1C), —OR^(1A), —NR^(1B)SO₂R^(1A),—NR^(1B)C(O)R^(1D), —NR^(1B)C(O)OR^(1D), —NR^(1B)OR^(1D), —OCX^(1.1) ₃,—OCHX^(1.1) ₂, substituted or unsubstituted alkyl, substituted orunsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl,substituted or unsubstituted heterocycloalkyl, substituted orunsubstituted aryl, or substituted or unsubstituted heteroaryl; R² ishydrogen, halogen, —CX^(2.1) ₃, —CHX^(2.1) ₂, —CH₂X^(2.1), —CN,—SO_(n2)R^(2A), —SO_(v2)NR^(2B)R^(2C), —NHNR^(2B)R^(2C),—ONR^(2B)R^(2C), —NHC(O)NHNR^(2B)R^(2C), —NHC(O)NR^(2B)R^(2C),—N(O)_(m2), —NR^(2B)R^(2C), —C(O)R^(2D), —C(O)OR^(2D),—C(O)NR^(2B)R^(2C), —OR^(2A), —NR^(2B)SO₂R^(2A), —NR^(2B)C(O)R^(2D),—NR^(2B)C(O)OR^(2D), —NR^(2B)OR^(2D), —OCX^(2.1) ₃, —OCHX^(2.1) ₂,substituted or unsubstituted alkyl, substituted or unsubstitutedheteroalkyl, substituted or unsubstituted cycloalkyl, substituted orunsubstituted heterocycloalkyl, substituted or unsubstituted aryl, orsubstituted or unsubstituted heteroaryl; R³ is hydrogen, halogen,—CX^(3.1) ₃, —CHX^(3.1) ₂, —CH₂X^(3.1), —CN, —SO_(n3)R^(3A),—SO_(v3)NR^(3B)R^(3C), —NHNR^(3B)R^(3C), —ONR^(3B)R^(3C),—NHC(O)NHNR^(3B)R^(3C), —NHC(O)NR^(3B)R^(3C), —N(O)_(m3),—NR^(3B)R^(3C), —C(O)R^(3D), —C(O)OR^(3D), —C(O)NR^(3B)R^(3C), —OR^(3A),—NR^(3B)SO₂R^(3A), —NR^(3B)C(O)R^(3D), —NR^(3B)C(O)OR^(3D),—NR^(3B)OR^(3D), —OCX^(3.1) ₃, —OCHX^(3.1) ₂, substituted orunsubstituted alkyl, substituted or unsubstituted heteroalkyl,substituted or unsubstituted cycloalkyl, substituted or unsubstitutedheterocycloalkyl, substituted or unsubstituted aryl, or substituted orunsubstituted heteroaryl; R⁴ is hydrogen, halogen, —CX^(4.1) ₃,—CHX^(4.1) ₂, —CH₂X^(4.1), —CN, —SO_(n4)R^(4A), —SO_(v4)NR^(4B)R^(4C),—NHNR^(4B)R^(4C), —ONR^(4B)R^(4C), —NHC(O)NHNR^(4B)R^(4C),—NHC(O)NR^(4B)R^(4C), —N(O)_(m4), —NR^(4B)R^(4C), —C(O)R^(4D),—C(O)OR^(4D), —C(O)NR^(4B)R^(4C), —OR^(4A), —NR^(4B)SO₂R^(4A),—NR^(4B)C(O)R^(4D), —NR^(4B)C(O)OR^(4D), —NR^(4B)OR^(4D), —OCX^(4.1) ₃,—OCHX^(4.1) ₂, substituted or unsubstituted alkyl, substituted orunsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl,substituted or unsubstituted heterocycloalkyl, substituted orunsubstituted aryl, or substituted or unsubstituted heteroaryl; R⁵ ishydrogen, halogen, —CX^(5.1) ₃, —CHX^(5.1) ₂, —CH₂X^(5.1), —CN,—SO_(n5)R^(5A), —SO_(v5)NR^(5B)R^(5C), —NHNR^(5B)R^(5C),—ONR^(5B)R^(5C), —NHC(O)NHNR^(5B)R^(5C), —NHC(O)NR^(5B)R^(5C),—N(O)_(m5), —NR^(5B)R^(5C), —C(O)R^(5D), —C(O)OR^(5D),—C(O)NR^(5B)R^(5C), —OR^(5A), —NR^(5B)SO₂R^(5A), —NR^(5B)C(O)R^(5D),—NR^(5B)C(O)OR^(5D), —NR^(5B)OR^(5D), —OCX^(5.1) ₃, —OCHX^(5.1) ₂,substituted or unsubstituted alkyl, substituted or unsubstitutedheteroalkyl, substituted or unsubstituted cycloalkyl, substituted orunsubstituted heterocycloalkyl, substituted or unsubstituted aryl, orsubstituted or unsubstituted heteroaryl; R^(1A), R^(1B), R^(1C), R^(1D),R^(2A), R^(2B), R^(2C), R^(2D), R^(3A), R^(3B), R^(3C), R^(3D), R^(4A),R^(4B), R^(4C), R^(4D), R^(5A), R^(5B), R^(5C) and R^(5D) areindependently hydrogen, halogen, —CF₃, —CCl₃, —CBr₃, —CI₃, —OH, —NH₂,—COOH, —CONH₂, —NO₂, —SH, —SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂, —ONH₂,—NHC(O)NHNH₂, —NHC(O)NH₂, —NHSO₂H, —NHC(O)H, —NHC(O)—OH, —NHOH, —OCF₃,—OCCl₃, —OCBr₃, —OCI₃, —OCHF₂, —OCHCl₂, —OCHBr₂, —OCHI₂, substituted orunsubstituted alkyl, substituted or unsubstituted heteroalkyl,substituted or unsubstituted cycloalkyl, substituted or unsubstitutedheterocycloalkyl, substituted or unsubstituted aryl, or substituted orunsubstituted heteroaryl; R^(1B), R^(1C), R^(2B), R^(2C), R^(3B),R^(3C), R^(4B), R^(4C), R^(5B) and R^(5C) substituents bonded to thesame nitrogen atom may optionally be joined to form a substituted orunsubstituted heterocycloalkyl or substituted or unsubstitutedheteroaryl; and X^(1.1), X^(2.1), X^(3.1), X^(4.1) and X^(5.1) areindependently —Cl, —Br, —I or —F.
 2. The method of claim 1, wherein: Aris unsubstituted heteroaryl; L¹ and L² are —CH₂—; and R¹, R², R³, R⁴ andR⁵ are independently hydrogen, —OCH₃ or —OCH₂CH₃.
 3. The method of claim2, wherein R¹, R⁴ and R⁵ are hydrogen.
 4. The method of claim 2, whereinR² and R³ are —OCH₃.
 5. The method of claim 2, wherein Ar isunsubstituted 2-thienyl.
 6. The method of claim 5, wherein the compoundis


7. The method of claim 1 wherein the compound of Formula I or apharmaceutically acceptable salt thereof is a compound of Formula IA:

or a pharmaceutically acceptable salt thereof, wherein: Ar issubstituted or unsubstituted aryl or substituted or unsubstitutedheteroaryl; L¹ and L² are independently substituted or unsubstitutedC₁-C₃ alkylene; n1, n2, n3, n4, n5, n6, n7, n8, n9 and n10 areindependently an integer from 0 to 4; m1, m2, m3, m4, m5, m6, m7, m8,m9, m10, v1, v2, v3, v4, v5, v6, v7, v8, v9 and v10 are independently 1or 2; R¹ is hydrogen, halogen, —CX^(1.1) ₃, —CHX^(1.1) ₂, —CH₂X^(1.1),—CN, —SO_(n1)R^(1A), —SO_(v1)NR^(1B)R^(1C), —NHNR^(1B)R^(1C),—ONR^(1B)R^(1C), —NHC(O)NHNR^(1B)R^(1C), —NHC(O)NR^(1B)R^(1C),—N(O)_(m1), —NR^(1B)R^(1C), —C(O)R^(1D), —C(O)OR^(1D),—C(O)NR^(1B)R^(1C), —OR^(1A), —NR^(1B)SO₂R^(1A), —NR^(1B)C(O)R^(1D),—NR^(1B)C(O)OR^(1D), —NR^(B)OR^(1D), —OCX^(1.1) ₃, —OCHX^(1.1) ₂,substituted or unsubstituted alkyl, substituted or unsubstitutedheteroalkyl, substituted or unsubstituted cycloalkyl, substituted orunsubstituted heterocycloalkyl, substituted or unsubstituted aryl, orsubstituted or unsubstituted heteroaryl; R² is hydrogen, halogen,—CX^(2.1) ₃, —CHX^(2.1) ₂, —CH₂X^(2.1), —CN, —SO_(n2)R^(2A),—SO_(v2)NR^(2B)R^(2C), —NHNR^(2B)R^(2C), —ONR^(2B)R^(2C),—NHC(O)NHNR^(2B)R^(2C), —NHC(O)NR^(2B)R^(2C), —N(O)_(m2),—NR^(2B)R^(2C), —C(O)R^(2D), —C(O)OR^(2D), —C(O)NR^(2B)R^(2C), —OR^(2A),—NR^(2B)SO₂R^(2A), —NR^(2B)C(O)R^(2D), —NR^(2B)C(O)OR^(2D),—NR^(2B)OR^(2D), —OCX^(2.1) ₃, —OCHX^(2.1) ₂, substituted orunsubstituted alkyl, substituted or unsubstituted heteroalkyl,substituted or unsubstituted cycloalkyl, substituted or unsubstitutedheterocycloalkyl, substituted or unsubstituted aryl, or substituted orunsubstituted heteroaryl; R³ is hydrogen, —CX^(3.1) ₃, —CHX^(3.1) ₂,—CH₂X^(3.1), —CN, —SO_(n3)R^(3A), —SO_(v3)NR^(3B)R^(3C),—NHNR^(3B)R^(3C), —ONR^(3B)R^(3C), —NHC(O)NHNR^(3B)R^(3C),—NHC(O)NR^(3B)R^(3C), —N(O)_(m3), —NR^(3B)R^(3C), —C(O)R^(3D),—C(O)OR^(3D), —C(O)NR^(3B)R^(3C), —OR^(3A), —NR^(3B)SO₂R^(3A),—NR^(3B)C(O)R^(3D), —NR^(3B)C(O)OR^(3D), —NR^(3B)OR^(3D), —OCX^(3.1) ₃,—OCHX^(3.1) ₂, substituted or unsubstituted alkyl, substituted orunsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl,substituted or unsubstituted heterocycloalkyl, substituted orunsubstituted aryl, or substituted or unsubstituted heteroaryl; R⁴ ishydrogen, halogen, —CX^(4.1) ₃, —CHX^(4.1) ₂, —CH₂X^(4.1), —CN,—SO_(n4)R^(4A), —SO_(v4)NR^(4B)R^(4C), —NHNR^(4B)R^(4C),—ONR^(4B)R^(4C), —NHC(O)NHNR^(4B)R^(4C), —NHC(O)NR^(4B)R^(4C),—N(O)_(m4), —NR^(4B)R^(4C), —C(O)R^(4D), —C(O)OR^(4D),—C(O)NR^(4B)R^(4C), —OR^(4A), —NR^(4B)SO₂R^(4A), —NR^(4B)C(O)R^(4D),—NR^(4B)C(O)OR^(4D), —NR^(4B)OR^(4D), —OCX^(4.1) ₃, —OCHX^(4.1) ₂,substituted or unsubstituted alkyl, substituted or unsubstitutedheteroalkyl, substituted or unsubstituted cycloalkyl, substituted orunsubstituted heterocycloalkyl, substituted or unsubstituted aryl, orsubstituted or unsubstituted heteroaryl; R⁵ is hydrogen, halogen,—CX^(5.1) ₃, —CHX^(5.1) ₂, —CH₂X^(5.1), —CN, —SO_(n5)R^(5A),—SO_(v5)NR^(5B)R^(5C), —NHNR^(5B)R^(5C), —ONR^(5B)R^(5C),—NHC(O)NHNR^(5B)R^(5C), —NHC(O)NR^(5B)R^(5C), —N(O)_(m5),—NR^(5B)R^(5C), —C(O)R^(5D), —C(O)OR^(5D), —C(O)NR^(5B)R^(5C), —OR^(5A),—NR^(5B)SO₂R^(5A), —NR^(5B)C(O)R^(5D), —NR^(5B)C(O)OR^(5D),—NR^(5B)OR^(5D), —OCX^(5.1) ₃, —OCHX^(5.1) ₂, substituted orunsubstituted alkyl, substituted or unsubstituted heteroalkyl,substituted or unsubstituted cycloalkyl, substituted or unsubstitutedheterocycloalkyl, substituted or unsubstituted aryl, or substituted orunsubstituted heteroaryl; R⁶ is hydrogen, halogen, —CX^(6.1) ₃,—CHX^(6.1) ₂, —CH₂X^(6.1), —CN, —SO_(n6)R^(6A), —SO_(v6)NR^(6B)R^(6C),—NHNR^(6B)R^(6C), —ONR^(6B)R^(6C), —NHC(O)NHNR^(6B)R^(6C),—NHC(O)NR^(6B)R^(6C), —N(O)_(m6), —NR^(6B)R^(6C), —C(O)R^(6D),—C(O)OR^(6D), —C(O)NR^(6B)R^(6C), —OR^(6A), —NR^(6B)SO₂R^(6A),—NR^(6B)C(O)R^(6D), —NR^(6B)C(O)OR^(6D), —NR^(6B)OR^(6D), —OCX^(6.1) ₃,—OCHX^(6.1) ₂, substituted or unsubstituted alkyl, substituted orunsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl,substituted or unsubstituted heterocycloalkyl, substituted orunsubstituted aryl, or substituted or unsubstituted heteroaryl; R⁷ ishydrogen, halogen, —CX^(7.1) ₃, —CHX^(7.1) ₂, —CH₂X^(7.1), —CN,—SO_(n7)R^(7A), —SO_(v7)NR^(7B)R^(7C), —NHNR^(7B)R^(7C),—ONR^(7B)R^(7C), —NHC(O)NHNR^(7B)R^(7C), —NHC(O)NR^(7B)R^(7C),—N(O)_(m7), —NR^(7B)R^(7C), —C(O)R^(7D), —C(O)OR^(7D),—C(O)NR^(7B)R^(7C), —OR^(7A), —NR^(7B)SO₂R^(7A), —NR^(7A)C(O)R^(7C),—NR^(7B)C(O)OR^(7D), —NR^(7B)OR^(7D), —OCX^(7.1) ₃, —OCHX^(7.1) ₂,substituted or unsubstituted alkyl, substituted or unsubstitutedheteroalkyl, substituted or unsubstituted cycloalkyl, substituted orunsubstituted heterocycloalkyl, substituted or unsubstituted aryl, orsubstituted or unsubstituted heteroaryl; R⁸ is hydrogen, halogen,—CX^(8.1) ₃, —CHX^(8.1) ₂, —CH₂X^(8.1), —CN, —SO_(n8)R^(8A),SO_(v5)NR^(8B)R^(8C), —NHNR^(8B)R^(8C), —ONR^(8B)R^(8C),—NHC(O)NHNR^(8B)R^(8C), —NHC(O)NR^(8B)R^(8C), —N(O)_(m8),—NR^(8B)R^(8C), —C(O)R^(8D), —C(O)OR^(8D), —C(O)NR^(8B)R^(8C), —OR^(8A),—NR^(8B)SO₂R^(8A), —NR^(8B)C(O)R^(8D), —NR^(8B)C(O)OR^(8D),—NR^(8B)OR^(8D), —OCX^(8.1) ₃, —OCHX^(8.1) ₂, substituted orunsubstituted alkyl, substituted or unsubstituted heteroalkyl,substituted or unsubstituted cycloalkyl, substituted or unsubstitutedheterocycloalkyl, substituted or unsubstituted aryl, or substituted orunsubstituted heteroaryl; R⁹ is hydrogen, halogen, —CX^(9.1) ₃,—CHX^(9.1) ₂, —CH₂X^(9.1), —CN, —SO_(n9)R^(9A), —SO_(v9)NR^(9B)R^(9C),—NHNR^(9B)R^(9C), —ONR^(9B)R^(9C), —NHC(O)NHNR^(9B)R^(9C),—NHC(O)NR^(9B)R^(9C), —N(O)_(m9), —NR^(9B)R^(9C), —C(O)R^(9D),—C(O)OR^(9D), —C(O)NR^(9B)R^(9C), —OR^(9A), —NR^(9B)SO₂R^(9A),—NR^(9B)C(O)R^(9D), —NR^(9B)C(O)OR^(9D), —NR^(9B)OR^(9D), —OCX^(9.1) ₃,—OCHX^(9.1) ₂, substituted or unsubstituted alkyl, substituted orunsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl,substituted or unsubstituted heterocycloalkyl, substituted orunsubstituted aryl, or substituted or unsubstituted heteroaryl; R¹⁰ ishydrogen, halogen, —CX^(10.1) ₃, —CHX^(10.1) ₂, —CH₂X^(10.1), —CN,—SO_(n10)R^(10A), SO_(v10)NR^(10B)R^(10C), —NHNR^(10B)R^(10C),—ONR^(10B)R^(10C), —NHC(O)NHNR^(10B)R^(10C), —NHC(O)NR^(10B)R^(10C),—N(O)_(m10), —NR^(10B)R^(10C), —C(O)R^(10D), —C(O)OR^(10D),—C(O)NR^(10B)R^(10C), —OR^(10A), —NR^(10B)SO₂R^(10A),—NR^(10B)C(O)R^(10D), —NR^(10B)C(O)OR^(10D), —NR^(10B)OR^(10D),—OCX^(10.1) ₃, —OCHX^(10.1) ₂, substituted or unsubstituted alkyl,substituted or unsubstituted heteroalkyl, substituted or unsubstitutedcycloalkyl, substituted or unsubstituted heterocycloalkyl, substitutedor unsubstituted aryl, or substituted or unsubstituted heteroaryl;R^(1A), R^(1B), R^(1C), R^(1D), R^(2A), R^(2B), R^(2C), R^(2D), R^(3A),R^(3B), R^(3C), R^(3D), R^(4A), R^(4B), R^(4C), R^(4D), R^(5A), R^(5B),R^(5C), R^(5D), R^(6A), R^(6B), R^(6C), R^(6D), R^(7A), R^(7B), R^(7C),R^(7D), R^(8A), R^(8B), R^(5C), R^(8D), R^(9A), R^(9B), R^(9C), R^(9D),R^(10A), R^(10B), R^(10C) and R^(10D) are independently hydrogen,halogen, —CF₃, —CCl₃, —CBr₃, —CI₃, —OH, —NH₂, —COOH, —CONH₂, —NO₂, —SH,—SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂, —ONH₂, —NHC(O)NHNH₂, —NHC(O)NH₂, —NHSO₂H,—NHC(O)H, —NHC(O)—OH, —NHOH, —OCF₃, —OCCl₃, —OCBr₃, —OCI₃, —OCHF₂,—OCHCl₂, —OCHBr₂, —OCHI₂, substituted or unsubstituted alkyl,substituted or unsubstituted heteroalkyl, substituted or unsubstitutedcycloalkyl, substituted or unsubstituted heterocycloalkyl, substitutedor unsubstituted aryl, or substituted or unsubstituted heteroaryl;R^(1B), R^(1C), R^(2B), R^(2C), R^(3B), R^(3C), R^(4B), R^(4C), R^(5B),R^(5C), R^(6B), R^(6C), R^(7B), R^(7C), R^(8B), R^(8C), R^(9B), R^(9C),R^(10B) and R^(10C) substituents bonded to the same nitrogen atom mayoptionally be joined to form a substituted or unsubstitutedheterocycloalkyl or substituted or unsubstituted heteroaryl; andX^(1.1), X^(2.1), X^(3.1), X^(4.1), X^(5.1), X^(6.1), X^(7.1), X^(8.1),X^(9.1) and X^(10.1) are independently —Cl, —Br, —I or —F, with provisothat when L¹ and L² are independently unsubstituted C₁-C₃ alkylene, R²and R³ are —OCH₃ and R⁷, R⁸, R⁹ and R¹⁰ are hydrogen, then R⁶ is not—OCH₃, or when L¹ and L² are independently unsubstituted C₁-C₃ alkylene,R² and R³ are —OCH₃, and R⁶, R⁸, R⁹ and R¹⁰ are hydrogen, then R⁷ is not—OCH₃.
 8. The method of claim 7, wherein: L¹ and L² are —CH₂—; R¹, R²,R⁴, R⁵, R⁶, R⁷, R⁸, R⁹ and R¹⁰ are independently hydrogen, halogen,—OCH₃ or —OCH₂CH₃; and R³ is hydrogen, —OCH₃ or —OCH₂CH₃.
 9. The methodof claim 7, wherein: L¹ and L² are —CH₂—; R², R³, R⁶ and R⁷ areindependently hydrogen, halogen, —OCH₃ or —OCH₂CH₃; R³ is hydrogen,—OCH₃ or —OCH₂CH₃; and R¹, R⁴, R⁵, R⁸, R⁹ and R¹⁰ are hydrogen.
 10. Themethod of claim 9, wherein R² and R³ are —OCH₃.
 11. The method of claim9, wherein R⁶ and R⁷ are independently chlorine or fluorine.
 12. Themethod of claim 9, wherein R⁶ is —OCH₂CH₃ and R⁷ is hydrogen.
 13. Themethod of claim 7, wherein the compound is:


14. The method of claim 1 wherein the compound is a compound selectedfrom the group consisting of:

or a pharmaceutically acceptable salt thereof.
 15. The method accordingto claim 1 wherein said disease or condition is constipation
 16. Themethod of claim 15, further comprising administering to the subject ananti-constipation agent.
 17. The method of claim 15, wherein thecompound is administered orally.
 18. The method of claim 15, wherein theconstipation is opioid-induced constipation, chronic idiopathicconstipation or irritable bowel syndrome with constipation predominance.19. The method of claim 15, 16, 17 or 18, wherein the compound isselected from the group consisting of:


20. The method according to claim 1 wherein said disease or condition isa dry eye disorder.
 21. The method of claim 20, wherein the dry eyedisorder is a lacrimal gland disorder.
 22. The method of claim 20,further comprising administering to the subject and anti-dry eye agent.23. The method of claim 20, wherein the compound is selected from thegroup consisting of:


24. A method of increasing lacrimation, comprising administering to asubject in need thereof an effective amount of a compound of structuralFormula (I):

or a pharmaceutically acceptable salt thereof, wherein: Ar issubstituted or unsubstituted aryl or substituted or unsubstitutedheteroaryl; L¹ and L² are independently substituted or unsubstitutedC₁-C₃ alkylene; n1, n2, n3, n4 and n5 are independently an integer from0 to 4; m1, m2, m3, m4, m5, v1, v2, v3, v4 and v5 are independently 1 or2; R¹ is hydrogen, halogen, —CX^(1.1) ₃, —CHX^(1.1) ₂, —CH₂X^(1.1), —CN,—SO_(n1)R^(1A), —SO_(v1)NR^(1B)R^(1C), —NHNR^(1B)R^(1C),—ONR^(1B)R^(1C), —NHC(O)NHNR^(1B)R^(1C), —NHC(O)NR^(1B)R^(1C),—N(O)_(m1), —NR^(1B)R^(1C), —C(O)R^(1D), —C(O)OR^(1D),—C(O)NR^(1B)R^(1C), —OR^(1A), —NR^(1B)SO₂R^(1A), —NR^(1B)C(O)R^(1D),—NR^(1B)C(O)OR^(1D), —NR^(1B)OR^(1D), —OCX^(1.1) ₃, —OCHX^(1.1) ₂,substituted or unsubstituted alkyl, substituted or unsubstitutedheteroalkyl, substituted or unsubstituted cycloalkyl, substituted orunsubstituted heterocycloalkyl, substituted or unsubstituted aryl, orsubstituted or unsubstituted heteroaryl; R² is hydrogen, halogen,—CX^(2.1) ₃, —CHX^(2.1) ₂, —CH₂X^(2.1), —CN, —SO_(n2)R^(2A),—SO_(v2)NR^(2B)R^(2C), —NHNR^(2B)R^(2C), —ONR^(2B)R^(2C),—NHC(O)NHNR^(2B)R^(2C), —NHC(O)NR^(2B)R^(2C), —N(O)_(m2),—NR^(2B)R^(2C), —C(O)R^(2D), —C(O)OR^(2D), —C(O)NR^(2B)R^(2C), —OR^(2A),—NR^(2B)SO₂R^(2A), —NR^(2B)C(O)R^(2D), —NR^(2B)C(O)OR^(2D),—NR^(2B)OR^(2D), —OCX^(2.1) ₃, —OCHX^(2.1) ₂, substituted orunsubstituted alkyl, substituted or unsubstituted heteroalkyl,substituted or unsubstituted cycloalkyl, substituted or unsubstitutedheterocycloalkyl, substituted or unsubstituted aryl, or substituted orunsubstituted heteroaryl; R³ is hydrogen, halogen, —CX^(3.1) ₃,—CHX^(3.1) ₂, —CH₂X^(3.1), —CN, —SO_(n3)R^(3A), —SO_(v3)NR^(3B)R^(3C),—NHNR^(3B)R^(3C), —ONR^(3B)R^(3C), —NHC(O)NHNR^(3B)R^(3C),—NHC(O)NR^(3B)R^(3C), —N(O)_(m3), —NR^(3B)R^(3C), —C(O)R^(3D),—C(O)OR^(3D), —C(O)NR^(3B)R^(3C), —OR^(3A), —NR^(3B)SO₂R^(3A),—NR^(3B)C(O)R^(3D), —NR^(3B)C(O)OR^(3D), —NR^(3B)OR^(3D), —OCX^(3.1) ₃,—OCHX^(3.1) ₂, substituted or unsubstituted alkyl, substituted orunsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl,substituted or unsubstituted heterocycloalkyl, substituted orunsubstituted aryl, or substituted or unsubstituted heteroaryl; R⁴ ishydrogen, halogen, —CX^(4.1) ₃, —CHX^(4.1) ₂, —CH₂X^(4.1), —CN,—SO_(n4)R^(4A), —SO_(v4)NR^(4B)R^(4C), —NHNR^(4B)R^(4C),—ONR^(4B)R^(4C), —NHC(O)NHNR^(4B)R^(4C), —NHC(O)NR^(4B)R^(4C),—N(O)_(m4), —NR^(4B)R^(4C), —C(O)R^(4D), —C(O)OR^(4D),—C(O)NR^(4B)R^(4C), —OR^(4A), —NR^(4B)SO₂R^(4A), —NR^(4B)C(O)R^(4D),—NR^(4B)C(O)OR^(4D), —NR^(4B)OR^(4D), —OCX^(4.1) ₃, —OCHX^(4.1) ₂,substituted or unsubstituted alkyl, substituted or unsubstitutedheteroalkyl, substituted or unsubstituted cycloalkyl, substituted orunsubstituted heterocycloalkyl, substituted or unsubstituted aryl, orsubstituted or unsubstituted heteroaryl; R⁵ is hydrogen, halogen,—CX^(5.1) ₃, —CHX^(5.1) ₂, —CH₂X^(5.1), —CN, —SO_(n5)R^(5A),—SO_(v5)NR^(5B)R^(5C), —NHNR^(5B)R^(5C), —ONR^(5B)R^(5C),—NHC(O)NHNR^(5B)R^(5C), —NHC(O)NR^(5B)R^(5C), —N(O)_(m5),—NR^(5B)R^(5C), —C(O)R^(5D), —C(O)OR^(5D), —C(O)NR^(5B)R^(5C), —OR^(5A),—NR^(5B)SO₂R^(5A), —NR^(5B)C(O)R^(5D), —NR^(5B)C(O)OR^(5D),—NR^(5B)OR^(5D), —OCX^(5.1) ₃, —OCHX^(5.1) ₂, substituted orunsubstituted alkyl, substituted or unsubstituted heteroalkyl,substituted or unsubstituted cycloalkyl, substituted or unsubstitutedheterocycloalkyl, substituted or unsubstituted aryl, or substituted orunsubstituted heteroaryl; R^(1A), R^(1B), R^(1C), R^(1D), R^(2A),R^(2B), R^(2C), R^(2D), R^(3A), R^(3B), R^(3C), R^(3D), R^(4A), R^(4B),R^(4C), R^(4D), R^(5A), R^(5B), R^(5C) and R^(5D) are independentlyhydrogen, halogen, —CF₃, —CCl₃, —CBr₃, —CI₃, —OH, —NH₂, —COOH, —CONH₂,—NO₂, —SH, —SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂, —ONH₂, —NHC(O)NHNH₂,—NHC(O)NH₂, —NHSO₂H, —NHC(O)H, —NHC(O)—OH, —NHOH, —OCF₃, —OCCl₃, —OCBr₃,—OCI₃, —OCHF₂, —OCHCl₂, —OCHBr₂, —OCHI₂, substituted or unsubstitutedalkyl, substituted or unsubstituted heteroalkyl, substituted orunsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl,substituted or unsubstituted aryl, or substituted or unsubstitutedheteroaryl; R^(1B), R^(1C), R^(2B), R^(2C), R^(3B), R^(3C), R^(4B),R^(4C), R^(5B) and R^(5C) substituents bonded to the same nitrogen atommay optionally be joined to form a substituted or unsubstitutedheterocycloalkyl or substituted or unsubstituted heteroaryl; andX^(1.1), X^(2.1), X^(3.1), X^(4.1) and X^(5.1) are independently —Cl,—Br, —I or —F.
 25. The method of claim 24, wherein the compound isselected from the group consisting of:


26. A method of activating Cystic Fibrosis Transmembrane ConductanceRegulator (CFTR), comprising contacting CFTR with an effective amount ofa compound of structural Formula (I):

or a pharmaceutically acceptable salt thereof, wherein: Ar issubstituted or unsubstituted aryl or substituted or unsubstitutedheteroaryl; L¹ and L² are independently substituted or unsubstitutedC₁-C₃ alkylene; n1, n2, n3, n4 and n5 are independently an integer from0 to 4; m1, m2, m3, m4, m5, v1, v2, v3, v4 and v5 are independently 1 or2; R¹ is hydrogen, halogen, —CX^(1.1) ₃, —CHX^(1.1) ₂, —CH₂X^(1.1), —CN,—SO_(n1)R^(1A), —SO_(v1)NR^(1B)R^(1C), —NHNR^(1B)R^(1C),—ONR^(1B)R^(1C), —NHC(O)NHNR^(1B)R^(1C), —NHC(O)NR^(1B)R^(1C),—N(O)_(m1), —NR^(1B)R^(1C), —C(O)R^(1D), —C(O)OR^(1D),—C(O)NR^(1B)R^(1C), —OR^(1A), —NR^(1B)SO₂R^(1A), —NR^(1B)C(O)R^(1D),—NR^(1B)C(O)OR^(1D), —NR^(1B)OR^(1D), —OCX^(1.1) ₃, —OCHX^(1.1) ₂,substituted or unsubstituted alkyl, substituted or unsubstitutedheteroalkyl, substituted or unsubstituted cycloalkyl, substituted orunsubstituted heterocycloalkyl, substituted or unsubstituted aryl, orsubstituted or unsubstituted heteroaryl; R² is hydrogen, halogen,—CX^(2.1) ₃, —CHX^(2.1) ₂, —CH₂X^(2.1), —CN, —SO_(n2)R^(2A),—SO_(v2)NR^(2B)R^(2C), —NHNR^(2B)R^(2C), —ONR^(2B)R^(2C),—NHC(O)NHNR^(2B)R^(2C), —NHC(O)NR^(2B)R^(2C), —N(O)_(m2),—NR^(2B)R^(2C), —C(O)R^(2D), —C(O)OR^(2D), —C(O)NR^(2B)R^(2C), —OR^(2A),—NR^(2B)SO₂R^(2A), —NR^(2B)C(O)R^(2D), —NR^(2B)C(O)OR^(2D),—NR^(2B)OR^(2D), —OCX^(2.1) ₃, —OCHX^(2.1) ₂, substituted orunsubstituted alkyl, substituted or unsubstituted heteroalkyl,substituted or unsubstituted cycloalkyl, substituted or unsubstitutedheterocycloalkyl, substituted or unsubstituted aryl, or substituted orunsubstituted heteroaryl; R³ is hydrogen, halogen, —CX^(3.1) ₃,—CHX^(3.1) ₂, —CH₂X^(3.1), —CN, —SO_(n3)R^(3A), —SO_(v3)NR^(3B)R^(3C),—NHNR^(3B)R^(3C), —ONR^(3B)R^(3C), —NHC(O)NHNR^(3B)R^(3C),—NHC(O)NR^(3B)R^(3C), —N(O)_(m3), —NR^(3B)R^(3C), —C(O)R^(3D),—C(O)OR^(3D), —C(O)NR^(3B)R^(3C), —OR^(3A), —NR^(3B)SO₂R^(3A),—NR^(3B)C(O)R^(3D), —NR^(3B)C(O)OR^(3D), —NR^(3B)OR^(3D), —OCX^(3.1) ₃,—OCHX^(3.1) ₂, substituted or unsubstituted alkyl, substituted orunsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl,substituted or unsubstituted heterocycloalkyl, substituted orunsubstituted aryl, or substituted or unsubstituted heteroaryl; R⁴ ishydrogen, halogen, —CX^(4.1) ₃, —CHX^(4.1) ₂, —CH₂X^(4.1), —CN,—SO_(n4)R^(4A), —SO_(v4)NR^(4B)R^(4C), —NHNR^(4B)R^(4C),—ONR^(4B)R^(4C), —NHC(O)NHNR^(4B)R^(4C), —NHC(O)NR^(4B)R^(4C),—N(O)_(m4), —NR^(4B)R^(4C), —C(O)R^(4D), —C(O)OR^(4D),—C(O)NR^(4B)R^(4C), —OR^(4A), —NR^(4B)SO₂R^(4A), —NR^(4B)C(O)R^(4D),—NR^(4B)C(O)OR^(4D), —NR^(4B)OR^(4D), —OCX^(4.1) ₃, —OCHX^(4.1) ₂,substituted or unsubstituted alkyl, substituted or unsubstitutedheteroalkyl, substituted or unsubstituted cycloalkyl, substituted orunsubstituted heterocycloalkyl, substituted or unsubstituted aryl, orsubstituted or unsubstituted heteroaryl; R⁵ is hydrogen, halogen,—CX^(5.1) ₃, —CHX^(5.1) ₂, —CH₂X^(5.1), —CN, —SO_(n5)R^(5A),—SO_(v5)NR^(5B)R^(5C), —NHNR^(5B)R^(5C), —ONR^(5B)R^(5C),—NHC(O)NHNR^(5B)R^(5C), —NHC(O)NR^(5B)R^(5C), —N(O)_(m5),—NR^(5B)R^(5C), —C(O)R^(5D), —C(O)OR^(5D), —C(O)NR^(5B)R^(5C), —OR^(5A),—NR^(5B)SO₂R^(5A), —NR^(5B)C(O)R^(5D), —NR^(5B)C(O)OR^(5D),—NR^(5B)OR^(5D), —OCX^(5.1) ₃, —OCHX^(5.1) ₂, substituted orunsubstituted alkyl, substituted or unsubstituted heteroalkyl,substituted or unsubstituted cycloalkyl, substituted or unsubstitutedheterocycloalkyl, substituted or unsubstituted aryl, or substituted orunsubstituted heteroaryl; R^(1A), R^(1B), R^(1C), R^(1D), R^(2A),R^(2B), R^(2C), R^(2D), R^(3A), R^(3B), R^(3C), R^(3D), R^(4A), R^(4B),R^(4C), R^(4D), R^(5A), R^(5B), R^(5C) and R^(5D) are independentlyhydrogen, halogen, —CF₃, —CCl₃, —CBr₃, —CI₃, —OH, —NH₂, —COOH, —CONH₂,—NO₂, —SH, —SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂, —ONH₂, —NHC(O)NHNH₂,—NHC(O)NH₂, —NHSO₂H, —NHC(O)H, —NHC(O)—OH, —NHOH, —OCF₃, —OCCl₃, —OCBr₃,—OCI₃, —OCHF₂, —OCHCl₂, —OCHBr₂, —OCHI₂, substituted or unsubstitutedalkyl, substituted or unsubstituted heteroalkyl, substituted orunsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl,substituted or unsubstituted aryl, or substituted or unsubstitutedheteroaryl; R^(1B), R^(1C), R^(2B), R^(2C), R^(3B), R^(3C), R^(4B),R^(4C), R^(5B) and R^(5C) substituents bonded to the same nitrogen atommay optionally be joined to form a substituted or unsubstitutedheterocycloalkyl or substituted or unsubstituted heteroaryl; andX^(1.1), X^(2.1), X^(3.1), X^(4.1) and X^(5.1) are independently —Cl,—Br, —I or —F.
 27. The method of claim 26, wherein the compound isselected from the group consisting of:


28. The method of claim 1 wherein said disease or condition ischolestatic liver disease.
 29. The method of claim 28, wherein thecompound is selected from the group consisting of:


30. The method according to claim 1 wherein said disease or condition isa pulmonary disease or disorder.
 31. The method of claim 30, wherein thepulmonary disease or disorder is chronic obstructive pulmonary disease,bronchitis, asthma, and cigarette smoke-induced lung dysfunction. 32.The method of claim 30, wherein the compound is selected from the groupconsisting of:

33.-48. (canceled)